84 replies to this topic

[Avatar of Horus]

continuing with some data on BMI1, heart, SASP and the skin, the mitochondria, with another aspect of aging: the mitochondrial DNA deletions.

A recent paper about a finding: BMI1 inhibits heart senescence too, and the accompanying SASP, and suggests it as a source for cardiac rejuvenation:

Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence
Gonzalez-Valdes et al. 2015
http://www.ncbi.nlm....pubmed/25751743

Abstract
Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation. Here we show that epigenetic regulator and central transcriptional instructor in adult stem cells, Bmi1, protects against DCM by repressing cardiac senescence. Cardiac-specific Bmi1 deletion induces the development of DCM, which progresses to lung congestion and heart failure. In contrast, Bmi1 overexpression in the heart protects from hypertrophic stimuli. Transcriptome analysis of mouse and human DCM samples indicates that p16(INK4a) derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16(INK4a) levels reverses the pathology of Bmi1-deficient hearts. In parabiosis assays, the paracrine senescence response underlying the DCM phenotype does not transmit to healthy mice. As senescence is implicated in tissue repair and the loss of regenerative potential in aging tissues, these findings suggest a source for cardiac rejuvenation.

 
About the mitochondria and mtDNA:
 
Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture
Rivera-Torres et al. 2013
http://www.ncbi.nlm....pubmed/23969228
 
about the regulation of the function of the mitochondria and the actin:
 
Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics
Beck et al. 2012
http://www.ncbi.nlm....pubmed/22927399
http://www.pnas.org/...9/38/E2523.full
 
Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics
Ho et al., Nature. 2013 May 23
http://www.ncbi.nlm....pubmed/23644458

PMC3666313

 

Earlier I presented this paper about fibroblasts and skin aging, and some dysfunctions in this process:
from the post #25:

... the "normal" aging of the skin, cf.:

Looking older: fibroblast collapse and therapeutic implications
Fisher, Varani, Voorhees, 2008
http://www.ncbi.nlm....pubmed/18490597

Abstract
Skin appearance is a primary indicator of age. During the last decade, substantial progress has been made toward understanding underlying mechanisms of human skin aging. This understanding provides the basis for current use and new development of antiaging treatments. Our objective is to review present state-of-the-art knowledge pertaining to mechanisms involved in skin aging, with specific focus on the dermal collagen matrix. A major feature of aged skin is fragmentation of the dermal collagen matrix. Fragmentation results from actions of specific enzymes (matrix metalloproteinases) and impairs the structural integrity of the dermis. Fibroblasts that produce and organize the collagen matrix cannot attach to fragmented collagen. Loss of attachment prevents fibroblasts from receiving mechanical information from their support, and they collapse. Stretch is critical for normal balanced production of collagen and collagen-degrading enzymes. In aged skin, collapsed fibroblasts produce low levels of collagen and high levels of collagen-degrading enzymes. This imbalance advances the aging process in a self-perpetuating, never-ending deleterious cycle. Clinically proven antiaging treatments such as topical retinoic acid, carbon dioxide laser resurfacing, and intradermal injection of cross-linked hyaluronic acid stimulate production of new, undamaged collagen. Attachment of fibroblasts to this new collagen allows stretch, which in turn balances collagen production and degradation and thereby slows the aging process. Collagen fragmentation is responsible for loss of structural integrity and impairment of fibroblast function in aged human skin. Treatments that stimulate production of new, nonfragmented collagen should provide substantial improvement to the appearance and health of aged skin.

...

 

Here is a subsequent one about the possible anti-aging effect of the corrections of
the mentioned dysfunctions, from the same group, in collaboration with another group:

Enhancing Structural Support of the Dermal Microenvironment Activates Fibroblasts, Endothelial Cells, and Keratinocytes in Aged Human Skin In Vivo
Taihao Quan1,2, Frank Wang1,2, Yuan Shao1, Laure Rittié1, Wei Xia1, Jeffrey S Orringer1, John J Voorhees1 and Gary J Fisher1
Journal of Investigative Dermatology (2013) 133,658–667; doi:10.1038/jid.2012.364; published online 25 October 2012
http://www.ncbi.nlm....pubmed/23096713
Abstract
The dermal extracellular matrix (ECM) provides strength and resiliency to skin. The ECM consists mostly of type I collagen fibrils, which are produced by fibroblasts. Binding of fibroblasts to collagen fibrils generates mechanical forces, which regulate cellular morphology and function. With aging, collagen fragmentation reduces fibroblast-ECM binding and mechanical forces, resulting in fibroblast shrinkage and reduced function, including collagen production. Here, we report that these age-related alterations are largely reversed by enhancing the structural support of the ECM. Injection of dermal filler, cross-linked hyaluronic acid, into the skin of individuals over 70 years of age stimulates fibroblasts to produce type I collagen. This stimulation is associated with localized increase in mechanical forces, indicated by fibroblast elongation/spreading, and mediated by upregulation of type II TGF-ß receptor and connective tissue growth factor. Interestingly, enhanced mechanical support of the ECM also stimulates fibroblast proliferation, expands vasculature, and increases epidermal thickness. Consistent with our observations in human skin, injection of filler into dermal equivalent cultures causes elongation of fibroblasts, coupled with type I collagen synthesis, which is dependent on the TGF-ß signaling pathway. Thus, fibroblasts in aged human skin retain their capacity for functional activation, which is restored by enhancing structural support of the ECM.

 
And another fresh result from the above collaborative group examining the problem of mitochondria and the actin in the skin.

Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging
Quan C1, Cho MK2, Perry D3, Quan T4.
J Biomed Sci. 2015 Jul 28;22(1):62. doi: 10.1186/s12929-015-0167-6.
http://www.ncbi.nlm....pubmed/26215577
Abstract
BACKGROUND:
Reduced cell spreading is a prominent feature of aged dermal fibroblasts in human skin in vivo. Mitochondrial DNA (mtDNA) common deletion has been reported to play a role in the human aging process, however the relationship between age-related reduced cell spreading and mtDNA common deletion has not yet been reported.
RESULTS:
To examine mtDNA common deletion in the dermis of aged human skin, the epidermis was removed from full-thickness human skin samples using cryostat. mtDNA common deletion was significantly elevated in the dermis of both naturally aged and photoaged human skin in vivo. To examine the relationship between age-related reduced cell spreading and mtDNA common deletion, we modulated the shape of dermal fibroblasts by disrupting the actin cytoskeleton. Reduced cell spreading was associated with a higher level of mtDNA common deletion and was also accompanied by elevated levels of endogenous reactive oxygen species (ROS). Boosting cellular antioxidant capacity by using antioxidants was found to be protective against mtDNA common deletion associated with reduced cell spreading.
CONCLUSION:
mtDNA common deletion is highly prevalent in the dermis of both naturally aged and photoaged human skin in vivo. mtDNA common deletion in response to reduced cell spreading is mediated, at least in part, by elevated oxidative stress in human dermal fibroblasts. These data extend current understanding of the mitochondrial theory of aging by identifying the connection between mtDNA common deletion and age-related reduction of cell spreading.

 
A comment about this paper from the BioscienceNews/fightaging blog:
http://www.longecity...-dna-deletions/

[Avatar of Horus]

I have finished with another round of sorting out some relevant infos about this unified theory of aging.
I divided the text into three posts; the first:

Some more words about the aging changes of the vasculature:

Elastin-elastase-atherosclerosis revisited
Robert et al. 1998
http://www.ncbi.nlm..../pubmed/9862271
Abstract
This review proposes reinvestigation of a topic studied in the author's laboratory over the last decades concerning the age-dependent modifications of the vascular extracellular matrix (ECM) as related to atherogenesis and its recognized risk-factors: blood lipids, lipoproteins. Most salient previous results are confronted with recent publications in this field. Age-dependent modifications of the vascular wall discussed in this review include upregulation of elastolytic enzymes, demonstrated for the first time in the vascular wall in this laboratory, matrix biosynthesis and receptor function. The progressive deposition of lipids in elastic tissues as well as the addition of lipoproteins or lipids to cell and organ cultures were shown to modify matrix biosynthesis and upregulate elastase expression. Lipid-elastin interactions exhibit a great deal of specificity as shown by the nature and amount of lipids accumulating in elastin in vivo and in vitro. Recent epidemiological studies (the EVA study) enables the confrontation of blood lipid parameters with matrix related components (serum elastase and inhibitors, elastin peptides, fibronectin) in the same blood samples. The elastin laminin receptor present on vascular cells was shown to trigger NO dependent vasodilation, and downregulation of cholesterol synthesis. Both of these functions decrease or disappear with age except the upregulation of elastase release which is preserved and increased. Recent experiments extended these findings to T-lymphocytes present also in the atherosclerotic plaque. Finally several recent publications are analyzed which give more precision on the cellular mechanisms underlying the above-described modifications.

 
So we have here several proteins, mentioned in this abstract, that deserves some investigations, the:
elastin, elastase, elastin-laminin receptor.
The elastin is degraged by elastase (more on this later),
and the
elastin-laminin receptor, which has another form, the:
Beta-galactosidase
which is widely used as a cell senescence biomarker, the gold standard, so to say:

A biomarker that identifies senescent human cells in culture and in aging skin in vivo
Dimri et al. 1995
http://www.ncbi.nlm..../pubmed/7568133
Abstract
Normal somatic cells invariably enter a state of irreversibly arrested growth and altered function after a finite number of divisions. This process, termed replicative senescence, is thought to be a tumor-suppressive mechanism and an underlying cause of aging. There is ample evidence that escape from senescence, or immortality, is important for malignant transformation. By contrast, the role of replicative senescence in organismic aging is controversial. Studies on cells cultured from donors of different ages, genetic backgrounds, or species suggest that senescence occurs in vivo and that organismic lifespan and cell replicative lifespan are under common genetic control. However, senescent cells cannot be distinguished from quiescent or terminally differentiated cells in tissues. Thus, evidence that senescent cells exist and accumulate with age in vivo is lacking. We show that several human cells express a beta-galactosidase, histochemically detectable at pH 6, upon senescence in culture. This marker was expressed by senescent, but not presenescent, fibroblasts and keratinocytes but was absent from quiescent fibroblasts and terminally differentiated keratinocytes. It was also absent from immortal cells but was induced by genetic manipulations that reversed immortality. In skin samples from human donors of different age, there was an age-dependent increase in this marker in dermal fibroblasts and epidermal keratinocytes. This marker provides in situ evidence that senescent cells may exist and accumulate with age in vivo.

 

Three other papers about cellular senescence in vitro and in in vivo, and its connection to the mentioned proteins in the previous posts:
RB,P16ink4a,and the lamins and actins, all of which seem to have a role in the aging process:
 
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy et al. 2004
http://www.ncbi.nlm....pubmed/15520862
 
Nuclear accumulation of globular actin as a cellular senescence marker
Kwak et al. 2004
http://www.ncbi.nlm....pubmed/14744771
 
Lamin B1 loss is a senescence-associated biomarker
Freund et al. 2012
http://www.ncbi.nlm....pubmed/22496421
 
and another novel marker for comparison:

α-Fucosidase as a novel convenient biomarker for cellular senescence
Hildebrand et al. 2013
http://www.ncbi.nlm....pubmed/23673343
Abstract
Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, there is currently no single specific marker that can unequivocally detect senescent cells. Here, we identified α-L-fucosidase (α-Fuc) as a novel sensitive biomarker for cellular senescence. Regardless of the stress stimulus and cell type, α-Fuc activity was induced in all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Strikingly, in most models the degree of α-Fuc upregulation was higher than the induction of senescence-associated β-galactosidase (SA-β-Gal), the current gold standard for senescence detection. As α-Fuc is convenient and easy to measure, we suggest its utility as a valuable marker, in particular in cells with low SA-β-Gal activity.

 
to be continued ...

[Avatar of Horus]

continuing from the previous post:

in this second part the starting point is this study, describing the effects of Zmpste24 deficiency, and its similarities with the physiological aging in rodents and humans:

Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease
Osorio et al. 2010
http://www.ncbi.nlm....pubmed/20961378
Abstract
Mutations in the nuclear envelope protein lamin A or in its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin A and develop multiple progeroid symptoms, thus representing a valuable animal model for the study of these syndromes. Zmpste24-deficient mice also show marked transcriptional alterations associated with chromatin disorganization, but the molecular links between both processes are unknown. We report herein that Zmpste24-deficient mice show a hypermethylation of rDNA that reduces the transcription of ribosomal genes, being this reduction reversible upon treatment with DNA methyltransferase inhibitors. This alteration has been previously described during physiological aging in rodents, suggesting its potential role in the development of the progeroid phenotypes. We also show that Zmpste24-deficient mice present global hypoacetylation of histones H2B and H4. By using a combination of RNA sequencing and chromatin immunoprecipitation assays, we demonstrate that these histone modifications are associated with changes in the expression of several genes involved in the control of cell proliferation and metabolic processes, which may contribute to the plethora of progeroid symptoms exhibited by Zmpste24-deficient mice. The identification of these altered genes may help to clarify the molecular mechanisms underlying aging and progeroid syndromes as well as to define new targets for the treatment of these dramatic diseases.

 
I would highlight here two proteins:
from Table 1: the Apcs and Orm1 (more on them in the next post and below).
 
The study mentions also the histone 4 hypoacetylation, some infos on this, and its connection to the normal aging:

Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice
Krishnan et al. 2011
http://www.ncbi.nlm....pubmed/21746928
Abstract
Specific point mutations in lamin A gene have been shown to accelerate aging in humans and mice. Particularly, a de novo mutation at G608G position impairs lamin A processing to produce the mutant protein progerin, which causes the Hutchinson Gilford progeria syndrome. The premature aging phenotype of Hutchinson Gilford progeria syndrome is largely recapitulated in mice deficient for the lamin A-processing enzyme, Zmpste24. We have previously reported that Zmpste24 deficiency results in genomic instability and early cellular senescence due to the delayed recruitment of repair proteins to sites of DNA damage. Here, we further investigate the molecular mechanism underlying delayed DNA damage response and identify a histone acetylation defect in Zmpste24(-/-) mice. Specifically, histone H4 was hypoacetylated at a lysine 16 residue (H4K16), and this defect was attributed to the reduced association of a histone acetyltransferase, Mof, to the nuclear matrix. Given the reversible nature of epigenetic changes, rescue experiments performed either by Mof overexpression or by histone deacetylase inhibition promoted repair protein recruitment to DNA damage sites and substantially ameliorated aging-associated phenotypes, both in vitro and in vivo. The life span of Zmpste24(-/-) mice was also extended with the supplementation of a histone deacetylase inhibitor, sodium butyrate, to drinking water. Consistent with recent data showing age-dependent buildup of unprocessable lamin A in physiological aging, aged wild-type mice also showed hypoacetylation of H4K16. The above results shed light on how chromatin modifications regulate the DNA damage response and suggest that the reversal of epigenetic marks could make an attractive therapeutic target against laminopathy-based progeroid pathologies.

 
Here also a possible life-extension method is mentioned: "The life span of Zmpste24(-/-) mice was also extended with the supplementation of a histone deacetylase inhibitor, sodium butyrate, to drinking water.", which extended the lifespan of these modified animals by about 15-20%. But as these changes seems to be present in wild-type animals, this may deserve further experimentation.

Like this one, about this and the actins and cell polarity (here the role of actins in the mitochondrial aging and cell senescence may be recalled from the two previous posts):

Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation
Florian et al. 2012
http://www.ncbi.nlm....pubmed/22560076
Abstract
The decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging.
 
Comment in:
Restoring cell polarity: an HSC fountain of youth
Carrillo-García & Janzen, 2012
http://www.ncbi.nlm....pubmed/22560067
Abstract
Until recently, aging was viewed as a fixed and irreversible process. However, in this issue of Cell Stem Cell, Florian et al. (2012) reveal a link between increased activity of the RhoGTPase Cdc42, hematopoietic stem cell polarity, and aging that can be regulated by pharmacological inhibition of Cdc42.

 
and to conclude this part:

A while back I've already mentioned a possibility about the prediction of the lifespan of an individual:

... as it is not only a measure of age, but also:

'Biological Clock' Found In DNA Could Predict How Long You're Going To Live
Researchers have discovered a biological clock that could help predict how long a person will live.
By Rebekah Marcarelli    Feb 02, 2015
http://www.hngn.com/...ing-to-live.htm

the paper of the research:

DNA methylation age of blood predicts all-cause mortality in later life
Marioni et al. 2015
http://www.ncbi.nlm....pubmed/25633388

...

 

Here is another similar thing, with the orosomucoid 1, ORM1 gene/protein, also known as the alpha-1-acid glycoprotein, which
"has been identified as one of four potentially useful circulating biomarkers for estimating the five-year risk of all-cause mortality (the other three are albumin, very low-density lipoprotein particle size, and citrate)." from Wikipedia,

https://en.wikipedia...iki/Orosomucoid
the study:
Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all-cause mortality: an observational study of 17,345 persons
Fischer et al. 2014
http://www.ncbi.nlm....pubmed/24586121

 

to be continued, with the amyloidosis ...

[Avatar of Horus]

continuation form the previous post, the third part:
about amyloidosis, and the Apcs protein, and elastase.
 
A possible connection with the SASP (e.g. interleukins) and AA amyloidosis:
Impaired degradation of serum amyloid A (SAA) protein by cytokine-stimulated monocytes
Migita et al. 2001
http://www.ncbi.nlm....pubmed/11298127

 
And, about the Apcs protein, also known as the SAP, serum amyloid P component, which seems to play a role in the various forms of amyloidosis diseases:
 
the MeSH gives the following informations about it:

Serum Amyloid P-Component
http://www.ncbi.nlm....v/mesh/68000683
Amyloid P component is a small, non-fibrillar glycoprotein found in normal serum and in all amyloid deposits. It has a pentagonal (pentaxin) structure. It is an acute phase protein, modulates immunologic responses, inhibits ELASTASE, and has been suggested as an indicator of LIVER DISEASE.

 

 

 

Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity
Bickerstaff MC, Botto M, Hutchinson WL, Herbert J, Tennent GA, Bybee A, Mitchell DA, Cook HT, Butler PJ, Walport MJ, Pepys MB.
Nat Med. 1999 Jun;5(6):694-7.
http://www.ncbi.nlm....pubmed/10371509

 

"Serum amyloid P component (SAP), a highly conserved plasma protein named for its universal presence in amyloid deposits, is the single normal circulating protein that shows specific calcium-dependent binding to DNA and chromatin in physiological conditions."

 
Human amyloid P component: an elastase inhibitor
Li JJ, McAdam KP.
Scand J Immunol. 1984 Sep;20(3):219-26.
http://www.ncbi.nlm..../pubmed/6568019
 
Inhibition of human neutrophil and Pseudomonas elastases by the amyloid P-component: a constituent of elastic fibers and amyloid deposits
Vachino et al. 1988
http://www.ncbi.nlm..../pubmed/3264008
 
Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis
Tennent GA, Lovat LB, Pepys MB.
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4299-303.
http://www.ncbi.nlm..../pubmed/7753801
 
Brain serum amyloid P levels are reduced in individuals that lack dementia while having Alzheimer's disease neuropathology
Crawford et al. 2012
http://www.ncbi.nlm....pubmed/22205573
 
Studies with radiolabelled serum amyloid P component provide evidence for turnover and regression of amyloid deposits in vivo
Hawkins 1994
http://www.ncbi.nlm..../pubmed/7955904
 
And, last but not least, a recent development, about an approach using the SAP protein for the removal of amyloid deposits:

Improving treatment for systemic amyloidosis
July 16, 2015
http://medicalxpress...myloidosis.html
 
A potential new approach to treat systemic amyloidosis, invented at UCL and being developed by GlaxoSmithKline (GSK), marks the start of a successful and innovative academic-industry collaboration.
 
The first in human clinical trial of a novel investigational drug intervention for patients with systemic amyloidosis has established proof of mechanism. Results in the first 15 patients treated with a therapeutic partnership of a small chemical molecule and a large biological molecule (an antibody) are published in the New England Journal of Medicine. Further clinical testing is in progress and a phase II trial to explore efficacy and safety is planned.
...

 

Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component
Richards DB1, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB.
N Engl J Med. 2015 Sep 17;373(12):1106-14. doi: 10.1056/NEJMoa1504942. Epub 2015 Jul 15.
http://www.ncbi.nlm....pubmed/26176329
Abstract
BACKGROUND: The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug ®-1-[6-[®-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells.
METHODS: We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored.
RESULTS: There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed.
CONCLUSIONS: Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).
http://clinicaltrial...how/NCT01777243

 

[Avatar of Horus]

A recent paper of a discovery about the similarity of laminopathies and age-related progressive neurodegenerative disorders:

 

Lamin Dysfunction Mediates Neurodegeneration in Tauopathies

Frost B, Bardai FH, Feany MB

Curr Biol. 2016 Jan 11

http://www.ncbi.nlm....pubmed/26725200

Abstract

The filamentous meshwork formed by the lamin nucleoskeleton provides a scaffold for the anchoring of highly condensed heterochromatic DNA to the nuclear envelope, thereby establishing the three-dimensional architecture of the genome [1]. Insight into the importance of lamins to cellular viability can be gleaned from laminopathies, severe disorders caused by mutations in genes encoding lamins. A cellular consequence of lamin dysfunction in laminopathies is relaxation of heterochromatic DNA [1]. Similarly, we have recently reported the widespread relaxation of heterochromatin in tauopathies [1]: age-related progressive neurodegenerative disorders, including Alzheimer's disease, that are pathologically characterized by aggregates of phosphorylated tau protein in the brain [2, 3]. Here we demonstrate that acquired lamin misregulation though aberrant cytoskeletal-nucleoskeletal coupling promotes relaxation of heterochromatin and neuronal death in an in vivo model of neurodegenerative tauopathy. Genetic manipulation of lamin function significantly modifies neurodegeneration in vivo, demonstrating that lamin pathology plays a causal role in tau-mediated neurotoxicity. We show that lamin dysfunction is conserved in human tauopathy, as super-resolution microscopy reveals a significantly disrupted nuclear lamina in postmortem tissue from human Alzheimer's disease brain. Our study provides strong evidence that tauopathies are neurodegenerative laminopathies and identifies a new pathway mediating neuronal death in currently untreatable human neurodegenerative disorders, including Alzheimer's disease.

 

 

[Never_Ending]

 

As explained in my poll thread in this forum, ageing is evolutionary purposeful, hydra can resist it, but without it, evolution for the species advances very slowly and into a "plant-like"(behaviour wise) direction(hydra, corals, jelly fish). I do believe the ceasing of stem cell immortality is purposeful for this reason rather than accidental as it seems the first life forms could retain it, it shouldn't have accidentally been lost, it just didn't lead to anything - evolutionary wise, it created a dead end. Ageing gives the body as a "disposable reproduction vehicle"(created as "behaviour" of the zygote and resulting cascading cell collective that is the body) a limited time to exist so this forces evolution of behaviour to *compete* for resources and reproduction(animal-lively-like) rather than *wait* for them and focus on survival/resistance/longevity(plant-like). If time is limited vehicles that perform better *per same life time* will spread more genes. If lime time is limited in an ingenious way(by stopping repairs rather than sudden death) natural selection of bodies/vehicles also remains meaningful although sudden death works to an extent as well but in species with large reproducing populations(insects, fish) which can spare the death toll of it. Stopping repairs is meaningful because it pushes for evolution of *behavior* rather than *form*. Behavior that spares the form after repairs cease prolongs life time of the form and thus reproduction time and so spreads more genes and thus is selected for. This pushes evolution of the nervous system rather than evolution of form as in tough shells, armour, expensive tough big clumsy stupid bodies. Time proves this is a wise choice. Pushing the nervous system results in the ability to increasingly adapt behaviour without DNA reconfiguration and finally results in ability to transfer behaviour without genetic transfer in mammals. The transfer and evolution of knowledge is again forced by ageing, young are full of zest for competition, knowledge and bettering it in relation to their parents and each other and are more unaware of danger, some progress and spread new better survival/thriving knowledge, some fail, those that survive spread genes are full of experience/fears which cause them to teach rather than do it further. This forces evolution of knowledge rather than strong form that would enforce wrong knowledge. Knowledge(of control) is a prize achievement of evolution as it allows evolution of behaviour(and spread of it) in a much more rapid way, without reconfiguring DNA. I do actually think nothing more needs to be said to explain the essence of ageing.

 

 

Although I do hear your point.... there are flaws in the reasoning.

 

Firstly... you mention aging as giving a limited time for evolution to select for reproduction. BUT a species with more time and equal reproductive abilities and zest will out compete a species with less time.

There is no "you're running out of time" motivation needed as more reproductive fitness dominates regardless

 

One more thing. Saying the body is a reproduction vehicle is misleading ... why? because evolution doesn't care if someone has 1 child that replaces them(turnover) or if they simply don't age while their DNA lives on that way. PROLIFERATION is the goal evolutionarily(having more and more kids and spreading the DNA sometimes at the Cost of the individual)...  Not turnover

 

Needless to say selection for reproduction is favored .. it eclipses selection for survival .   Add in antagonistic pleiotropy and the materials for aging are all there. And evolution sees no need to fix the issue  

But it's important to remember within each sexually reproducing creature is a non-sexual survival creature... Although some weak passive forces that ease away repairs might exist , for the most part evolution "Doesn't care" as long as the DNA lives on in someone(even if it's the original creature). as long as a stronger creature doesn't kill them off

Edited by Never_Ending, 16 February 2016 - 04:07 PM.

[addx]

 

 

As explained in my poll thread in this forum, ageing is evolutionary purposeful, hydra can resist it, but without it, evolution for the species advances very slowly and into a "plant-like"(behaviour wise) direction(hydra, corals, jelly fish). I do believe the ceasing of stem cell immortality is purposeful for this reason rather than accidental as it seems the first life forms could retain it, it shouldn't have accidentally been lost, it just didn't lead to anything - evolutionary wise, it created a dead end. Ageing gives the body as a "disposable reproduction vehicle"(created as "behaviour" of the zygote and resulting cascading cell collective that is the body) a limited time to exist so this forces evolution of behaviour to *compete* for resources and reproduction(animal-lively-like) rather than *wait* for them and focus on survival/resistance/longevity(plant-like). If time is limited vehicles that perform better *per same life time* will spread more genes. If lime time is limited in an ingenious way(by stopping repairs rather than sudden death) natural selection of bodies/vehicles also remains meaningful although sudden death works to an extent as well but in species with large reproducing populations(insects, fish) which can spare the death toll of it. Stopping repairs is meaningful because it pushes for evolution of *behavior* rather than *form*. Behavior that spares the form after repairs cease prolongs life time of the form and thus reproduction time and so spreads more genes and thus is selected for. This pushes evolution of the nervous system rather than evolution of form as in tough shells, armour, expensive tough big clumsy stupid bodies. Time proves this is a wise choice. Pushing the nervous system results in the ability to increasingly adapt behaviour without DNA reconfiguration and finally results in ability to transfer behaviour without genetic transfer in mammals. The transfer and evolution of knowledge is again forced by ageing, young are full of zest for competition, knowledge and bettering it in relation to their parents and each other and are more unaware of danger, some progress and spread new better survival/thriving knowledge, some fail, those that survive spread genes are full of experience/fears which cause them to teach rather than do it further. This forces evolution of knowledge rather than strong form that would enforce wrong knowledge. Knowledge(of control) is a prize achievement of evolution as it allows evolution of behaviour(and spread of it) in a much more rapid way, without reconfiguring DNA. I do actually think nothing more needs to be said to explain the essence of ageing.

 

 

Although I do hear your point.... there are flaws in the reasoning.

 

Firstly... you mention aging as giving a limited time for evolution to select for reproduction. BUT a species with more time and equal reproductive abilities and zest will out compete a species with less time.

There is no "you're running out of time" motivation needed as more reproductive fitness dominates regardless

 

One more thing. Saying the body is a reproduction vehicle is misleading ... why? because evolution doesn't care if someone has 1 child that replaces them(turnover) or if they simply don't age while their DNA lives on that way. PROLIFERATION is the goal evolutionarily(having more and more kids and spreading the DNA sometimes at the Cost of the individual)...  Not turnover

 

Needless to say selection for reproduction is favored .. it eclipses selection for survival .   Add in antagonistic pleiotropy and the materials for aging are all there. And evolution sees no need to fix the issue  

But it's important to remember within each sexually reproducing creature is a non-sexual survival creature... Although some weak passive forces that ease away repairs might exist , for the most part evolution "Doesn't care" as long as the DNA lives on in someone(even if it's the original creature). as long as a stronger creature doesn't kill them off

 

 

 

 

 

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

Edited by addx, 17 February 2016 - 09:10 AM.

[niner]

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

 

This is internally consistent, but doesn't it make the assumption that the beginning state was animals that don't age, or don't age much?  It's hard to make animals that live a long time-- They need all sorts of elaborate repair mechanisms.  It seems far more likely that early organisms aged rapidly, and only evolved longer lives if it improved reproductive fitness.  In an environment of predation and infection, animals didn't need any extra help dying, so I don't see a driving force for evolution of aging.

[Never_Ending]

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms.

 

Yea but "outcompete" is vague ... evolution doesnt care about advancement it only cares about survival and adaptation. Thats why rabbits are still rabbits they dont become humans because they are stable in their own way. So if the 50 eternals are fit enough to survive there is no difference to the 50 agers. Also if the 50 eternals have the same reproductive skills they can still make more variation and proliferation.

 

I guess what you said speaks to a limited resource scenario and one where competition results in a net loss, that's the only case and is not so much true in many natural scenarios

Edited by Never_Ending, 18 February 2016 - 01:35 AM.

[corb]

 

 

 

As explained in my poll thread in this forum, ageing is evolutionary purposeful, hydra can resist it, but without it, evolution for the species advances very slowly and into a "plant-like"(behaviour wise) direction(hydra, corals, jelly fish). I do believe the ceasing of stem cell immortality is purposeful for this reason rather than accidental as it seems the first life forms could retain it, it shouldn't have accidentally been lost, it just didn't lead to anything - evolutionary wise, it created a dead end. Ageing gives the body as a "disposable reproduction vehicle"(created as "behaviour" of the zygote and resulting cascading cell collective that is the body) a limited time to exist so this forces evolution of behaviour to *compete* for resources and reproduction(animal-lively-like) rather than *wait* for them and focus on survival/resistance/longevity(plant-like). If time is limited vehicles that perform better *per same life time* will spread more genes. If lime time is limited in an ingenious way(by stopping repairs rather than sudden death) natural selection of bodies/vehicles also remains meaningful although sudden death works to an extent as well but in species with large reproducing populations(insects, fish) which can spare the death toll of it. Stopping repairs is meaningful because it pushes for evolution of *behavior* rather than *form*. Behavior that spares the form after repairs cease prolongs life time of the form and thus reproduction time and so spreads more genes and thus is selected for. This pushes evolution of the nervous system rather than evolution of form as in tough shells, armour, expensive tough big clumsy stupid bodies. Time proves this is a wise choice. Pushing the nervous system results in the ability to increasingly adapt behaviour without DNA reconfiguration and finally results in ability to transfer behaviour without genetic transfer in mammals. The transfer and evolution of knowledge is again forced by ageing, young are full of zest for competition, knowledge and bettering it in relation to their parents and each other and are more unaware of danger, some progress and spread new better survival/thriving knowledge, some fail, those that survive spread genes are full of experience/fears which cause them to teach rather than do it further. This forces evolution of knowledge rather than strong form that would enforce wrong knowledge. Knowledge(of control) is a prize achievement of evolution as it allows evolution of behaviour(and spread of it) in a much more rapid way, without reconfiguring DNA. I do actually think nothing more needs to be said to explain the essence of ageing.

 

 

Although I do hear your point.... there are flaws in the reasoning.

 

Firstly... you mention aging as giving a limited time for evolution to select for reproduction. BUT a species with more time and equal reproductive abilities and zest will out compete a species with less time.

There is no "you're running out of time" motivation needed as more reproductive fitness dominates regardless

 

One more thing. Saying the body is a reproduction vehicle is misleading ... why? because evolution doesn't care if someone has 1 child that replaces them(turnover) or if they simply don't age while their DNA lives on that way. PROLIFERATION is the goal evolutionarily(having more and more kids and spreading the DNA sometimes at the Cost of the individual)...  Not turnover

 

Needless to say selection for reproduction is favored .. it eclipses selection for survival .   Add in antagonistic pleiotropy and the materials for aging are all there. And evolution sees no need to fix the issue  

But it's important to remember within each sexually reproducing creature is a non-sexual survival creature... Although some weak passive forces that ease away repairs might exist , for the most part evolution "Doesn't care" as long as the DNA lives on in someone(even if it's the original creature). as long as a stronger creature doesn't kill them off

 

 

 

 

 

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

 

 

A young cohort and an old cohort competing on equal grounds provides more competition.
Whether you're looking at adaptability or speed of evolution that would produce better results.

And it does produce better results - see bacteria.

 

I had written a long answer but decided this short one is much better and drives the point home perfectly.

Edited by corb, 18 February 2016 - 04:30 AM.

[addx]

 

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

 

This is internally consistent, but doesn't it make the assumption that the beginning state was animals that don't age, or don't age much?  It's hard to make animals that live a long time-- They need all sorts of elaborate repair mechanisms.  It seems far more likely that early organisms aged rapidly, and only evolved longer lives if it improved reproductive fitness.  In an environment of predation and infection, animals didn't need any extra help dying, so I don't see a driving force for evolution of aging.

 

 

 

 

Single cell life forms are pretty much immortal. Ageing developed in tandem with multicellularity and sexual reproduction in animals. 

 

First multicellular lifeforms simply kept their "offspring" cells attached to them and this created primitive bodies. Eventually the attached offspring cells differentiated to form different tissues via parent cells leaking "enslaving"(differentiating) chemicals in a timed/triggered manner etc. This process of "growing (fruiting) bodies" eventually evolved into very complex proliferation sequences and within it - ageing developed - as a part of the sequence - the life cycle.

 

Similarly to the way multicellular body plan (how many legs/hand/segments etc) is determined by a set of HOX genes in basicly all animals https://en.wikipedia.org/wiki/Hox_gene, so is the lifecycle of the multicellular body determined by a set of FOX genes https://en.wikipedia...ki/FOX_proteins in all of them. 

 

First multicellular animals didn't age rapidly, quite the contrary. The most primitive animal species we still have present today are often immortal or long lived - the most prominent are hydras or corals. As the evolutionary tree of life branched out - it became harder and harder for "immortal" animals to survive the competition from ageing animals within rich niches that can sustain a lot of turnover. It also became increasingly hard to for complex bodies to make large scale repairs from physical damage. It's one thing to grow a tentacle, but an entirely different thing to grow an arm with skeleton, knuckles, joints and muscles properly attached and innervated. It also became increasingly hard to sustain ever growing bodies (like the crustaceans among which there are some that also seem to grow and live indefinitely) as the vast differences in size require differences in behavior, different food etc.

 

And you are right, pressure from predators is similar to ageing pressure, but still, ageing enhances pressure from predators and makes for even better selection - against predators! If you have enough bodies to throw at it, why would this mechanism not evolve? Think long term... 
If you have a system that produces steady evolution (species with sexual reproduction are exactly that) then you expect to have "better"/"more evolved" offspring than their parents (on average). If your offspring is expected to be more evolved why not kill off the parents in this ingenious way that provides more selection (and releases more resources/food for the young offspring - animals sometimes do need help dying, if they want to make room for their more evolved offspring)? 
As body repairs are slowly stopped to a halt, the parent still has some fighting chance, depending on how good his final/mature state was. If it was good he'll survive a bit longer than some other member of the same species and make a few extra offspring in his lifetime thanks to his other important "niche abilities" which his species actively evolves, rather than general endless repair ability which evolved millions of years ago and was since "shunned" by most species. These few extra offspring will provide more spread of his proven and able genes that warrant a good final/mature state..... if the final/mature state developed from his genes was not good he'll die off faster as he begins to age and will not make the extra few offspring.

 

Species with most turnover produce most evolution: insects, fish, krill, season plants etc. The sheer number of species that evolved along those lineages is overwhelming and so is the even bigger number of already extinct species! Species with least turnover are usually "evolutionary" oldest in a sense - they are the same now as they were millions of years ago - living fossils.

[addx]

 

 

 

 

As explained in my poll thread in this forum, ageing is evolutionary purposeful, hydra can resist it, but without it, evolution for the species advances very slowly and into a "plant-like"(behaviour wise) direction(hydra, corals, jelly fish). I do believe the ceasing of stem cell immortality is purposeful for this reason rather than accidental as it seems the first life forms could retain it, it shouldn't have accidentally been lost, it just didn't lead to anything - evolutionary wise, it created a dead end. Ageing gives the body as a "disposable reproduction vehicle"(created as "behaviour" of the zygote and resulting cascading cell collective that is the body) a limited time to exist so this forces evolution of behaviour to *compete* for resources and reproduction(animal-lively-like) rather than *wait* for them and focus on survival/resistance/longevity(plant-like). If time is limited vehicles that perform better *per same life time* will spread more genes. If lime time is limited in an ingenious way(by stopping repairs rather than sudden death) natural selection of bodies/vehicles also remains meaningful although sudden death works to an extent as well but in species with large reproducing populations(insects, fish) which can spare the death toll of it. Stopping repairs is meaningful because it pushes for evolution of *behavior* rather than *form*. Behavior that spares the form after repairs cease prolongs life time of the form and thus reproduction time and so spreads more genes and thus is selected for. This pushes evolution of the nervous system rather than evolution of form as in tough shells, armour, expensive tough big clumsy stupid bodies. Time proves this is a wise choice. Pushing the nervous system results in the ability to increasingly adapt behaviour without DNA reconfiguration and finally results in ability to transfer behaviour without genetic transfer in mammals. The transfer and evolution of knowledge is again forced by ageing, young are full of zest for competition, knowledge and bettering it in relation to their parents and each other and are more unaware of danger, some progress and spread new better survival/thriving knowledge, some fail, those that survive spread genes are full of experience/fears which cause them to teach rather than do it further. This forces evolution of knowledge rather than strong form that would enforce wrong knowledge. Knowledge(of control) is a prize achievement of evolution as it allows evolution of behaviour(and spread of it) in a much more rapid way, without reconfiguring DNA. I do actually think nothing more needs to be said to explain the essence of ageing.

 

 

Although I do hear your point.... there are flaws in the reasoning.

 

Firstly... you mention aging as giving a limited time for evolution to select for reproduction. BUT a species with more time and equal reproductive abilities and zest will out compete a species with less time.

There is no "you're running out of time" motivation needed as more reproductive fitness dominates regardless

 

One more thing. Saying the body is a reproduction vehicle is misleading ... why? because evolution doesn't care if someone has 1 child that replaces them(turnover) or if they simply don't age while their DNA lives on that way. PROLIFERATION is the goal evolutionarily(having more and more kids and spreading the DNA sometimes at the Cost of the individual)...  Not turnover

 

Needless to say selection for reproduction is favored .. it eclipses selection for survival .   Add in antagonistic pleiotropy and the materials for aging are all there. And evolution sees no need to fix the issue  

But it's important to remember within each sexually reproducing creature is a non-sexual survival creature... Although some weak passive forces that ease away repairs might exist , for the most part evolution "Doesn't care" as long as the DNA lives on in someone(even if it's the original creature). as long as a stronger creature doesn't kill them off

 

 

 

 

 

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

 

 

A young cohort and an old cohort competing on equal grounds provides more competition.
Whether you're looking at adaptability or speed of evolution that would produce better results.

And it does produce better results - see bacteria.

 

I had written a long answer but decided this short one is much better and drives the point home perfectly.

 

 

You have to keep in mind that for most animals - old cohorts means bigger/stronger individuals against which the young cohorts can't win. This is very similar to trees/forests. A young tree can not grow in the shade of its parent. The forest must expand, if there's no room, turnover/evolution of that tree species grinds to a halt. For trees it is more prudent to keep the territory they grow in rather than to die off for turnover and its future benefits and risk some other plant growing in it before the offspring manages to...But for animals it often isn't smart to do so. An animal has to actively seek out and/or fight for its resources while a tree simply grows on it and is passive in its behavior.

Sexual reproduction (a system for slow and steady evolution) doesn't produce jumps in evolution but rather small increments.

If you're creating a situation where a youngster must defeat a biologically immortal parent in some way to get his place under the sun (there we go with trees again), you're "selecting" for a large genetic jump, not for small increments! Only a vastly different offspring will be able to survive - to push out/defeat his larger/stronger/more experienced parent.

So, without ageing, the immortal parents will not allow much room for offspring. If the food supply can not be expanded (the forest can't grow), the offspring will not survive. 

It's not the same as with single cell life forms where the age or the "maturehood" of the single cell does not make it any stronger, it does not grow muscles or shells or storages of food within it or whatever.

I am interested in whatever experiment with bacteria you had in mind though, I've read a couple and they were quite interesting. What does young vs old cohort mean anyway? They take out some bacteria out of the evolving petri dish at some point, freeze it, have the other bacteria evolve for a while and then reintroduce the frozen bacteria as the "old cohort"?

Edited by addx, 18 February 2016 - 01:31 PM.

[addx]

 

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms.

 

Yea but "outcompete" is vague ... evolution doesnt care about advancement it only cares about survival and adaptation. Thats why rabbits are still rabbits they dont become humans because they are stable in their own way. So if the 50 eternals are fit enough to survive there is no difference to the 50 agers. Also if the 50 eternals have the same reproductive skills they can still make more variation and proliferation.

 

I guess what you said speaks to a limited resource scenario and one where competition results in a net loss, that's the only case and is not so much true in many natural scenarios

 

 

You're right!

Immortals win in that scenario I posted.

 

Immortals only lose if the mortals are allowed to evolve separately for some time and then get exposed to them. Immortals will then become extinct via competition for resources/starvation by the more able, yet mortal cousins. 

[corb]

 

 

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

 

This is internally consistent, but doesn't it make the assumption that the beginning state was animals that don't age, or don't age much?  It's hard to make animals that live a long time-- They need all sorts of elaborate repair mechanisms.  It seems far more likely that early organisms aged rapidly, and only evolved longer lives if it improved reproductive fitness.  In an environment of predation and infection, animals didn't need any extra help dying, so I don't see a driving force for evolution of aging.

 

 

 

 

Single cell life forms are pretty much immortal. Ageing developed in tandem with multicellularity and sexual reproduction in animals. 

 

First multicellular lifeforms simply kept their "offspring" cells attached to them and this created primitive bodies. Eventually the attached offspring cells differentiated to form different tissues via parent cells leaking "enslaving"(differentiating) chemicals in a timed/triggered manner etc. This process of "growing (fruiting) bodies" eventually evolved into very complex proliferation sequences and within it - ageing developed - as a part of the sequence - the life cycle.

 

Similarly to the way multicellular body plan (how many legs/hand/segments etc) is determined by a set of HOX genes in basicly all animals https://en.wikipedia.org/wiki/Hox_gene, so is the lifecycle of the multicellular body determined by a set of FOX genes https://en.wikipedia...ki/FOX_proteins in all of them. 

 

First multicellular animals didn't age rapidly, quite the contrary. The most primitive animal species we still have present today are often immortal or long lived - the most prominent are hydras or corals. As the evolutionary tree of life branched out - it became harder and harder for "immortal" animals to survive the competition from ageing animals within rich niches that can sustain a lot of turnover. It also became increasingly hard to for complex bodies to make large scale repairs from physical damage. It's one thing to grow a tentacle, but an entirely different thing to grow an arm with skeleton, knuckles, joints and muscles properly attached and innervated. It also became increasingly hard to sustain ever growing bodies (like the crustaceans among which there are some that also seem to grow and live indefinitely) as the vast differences in size require differences in behavior, different food etc.

 

And you are right, pressure from predators is similar to ageing pressure, but still, ageing enhances pressure from predators and makes for even better selection - against predators! If you have enough bodies to throw at it, why would this mechanism not evolve? Think long term... 
If you have a system that produces steady evolution (species with sexual reproduction are exactly that) then you expect to have "better"/"more evolved" offspring than their parents (on average). If your offspring is expected to be more evolved why not kill off the parents in this ingenious way that provides more selection (and releases more resources/food for the young offspring - animals sometimes do need help dying, if they want to make room for their more evolved offspring)? 
As body repairs are slowly stopped to a halt, the parent still has some fighting chance, depending on how good his final/mature state was. If it was good he'll survive a bit longer than some other member of the same species and make a few extra offspring in his lifetime thanks to his other important "niche abilities" which his species actively evolves, rather than general endless repair ability which evolved millions of years ago and was since "shunned" by most species. These few extra offspring will provide more spread of his proven and able genes that warrant a good final/mature state..... if the final/mature state developed from his genes was not good he'll die off faster as he begins to age and will not make the extra few offspring.

 

Species with most turnover produce most evolution: insects, fish, krill, season plants etc. The sheer number of species that evolved along those lineages is overwhelming and so is the even bigger number of already extinct species! Species with least turnover are usually "evolutionary" oldest in a sense - they are the same now as they were millions of years ago - living fossils.

 

 

It's exactly when you look at this in the long run that it doesn't pan out.
An enhanced turnover doesn't guarantee enhanced adaptability or enhanced survival. It guarantees enhanced turn over. And that's all.

Since evolution is a random process you can throw millions or random variants at a problem that doesn't guarantee you'll ever get a robust answer to that problem. If you lose superior variants through timed culling of the population you're actually slowing down the process rather than speeding it up.

This is why viruses and bacteria will always outsmart our immune systems.

Also when you think of competition between cohorts you have to remember most multicelular life does not have direct competition between parent and child. Their competition will come from survival and proliferation in their environment.

Another thing as Never_Ending points out - performance is a vague measure in evolution, a human concept. As long as a species is capable of survival in it's environment there is little to no selective pressure. Does a forced turn over jump over this problem? Actually no, it's the opposite. The only competition that can come once a species is stable like that is from old cohorts competing against young cohorts.

Which is why eventually the top of the food pyramid was taken up by long lived predators like us.

 

You're actually closer to the truth when you're saying it's harder to end up with robust repair mechanisms the bigger (arguably if it's more complex) the organism is. It is harder and there is little selective pressure to achieve it, but once the species is in a stable place in it's environment the selective pressure for longer lives is there. All long lived species are either apex predators or species which are almost immune to predation - Elephants, whales, big cats, birds, bears.

Which is the opposite of what you're saying! If there was an intrinsic benefit to a high turn over nature would be pushing shorter lifespans on these otherwise quite stable species. It's not.
As a great example - Alligators have remained virtually the same for 200 to 250 million years. Yet can live up to 55 years.

 

So in my view aging started out as a defect which was not removed because it's a slow process. But as species reach the apex their only competition comes from within the species. At that point the pressure for longer lives is stronger and these species evolve repair mechanisms. There is no aging gene to look for. There's a plethora of small deficits which nature has overlooked for hundreds of millions of years. Luckily for us we are the apex of the apex so we already have quite a few repair mechanism beyond mice and flies.

 

And by the way I won't bother looking up how you ended up talking about your evolutionary theories again but please don't mess up the thread. If you want to talk evolution open up another thread.

Edited by corb, 18 February 2016 - 01:59 PM.

[addx]

It's exactly when you look at this in the long run that it doesn't pan out.
An enhanced turnover doesn't guarantee enhanced adaptability or enhanced survival. It guarantees enhanced turn over. And that's all.


Since evolution is a random process you can throw millions or random variants at a problem that doesn't guarantee you'll ever get a robust answer to that problem.

If you lose superior variants through timed culling of the population you're actually slowing down the process rather than speeding it up.

This is why viruses and bacteria will always outsmart our immune systems.

Also when you think of competition between cohorts you have to remember most multicelular life does not have direct competition between parent and child. Their competition will come from survival and proliferation in their environment.

Another thing as Never_Ending points out - performance is a vague measure in evolution, a human concept. As long as a species is capable of survival in it's environment there is little to no selective pressure.

Enhanced turnover guarantees more evolution, more and faster adaptation to circumstances. Lineages with high turnover have evolved most species and have extinct most species. It doesnt mean all that evolution was "very meaningful" and compounded to produce some "super species" which "has it all". It means the lineage adapted many times to different circumstances - most of which were created by the species themselves. It did not nesessarily "advance" in some obvious sense.

Species with high turnover are the most robust "life organizations" that will survive and adapt to grossly and rapidly changing circumstances. Most of your apex predators will be the first to get extinct if there's just a minor shift in their ecosystem, while most high turnover species will adapt and survive in some way. The slower the turnover the slower the species can adapt to changing ecosystems. And ecosystems change, have always and will always.

Evolution is also not an entirely random process (it is quite directed in fact) and even if it was: producing millions of random variants is always better than producing less than that random variants. More can be selected from a million than from a thousand.
 
With ageing - you still lose inferior variants faster than superior variants. You also rescue immature superior variants from being starved or pushed aside by selfish mature inferior variants.

Interestingly, immune systems of animals "evolve" against viruses and bacteria during their lifetime and are able to pass on the evolved knowledge to progeny.

Since the abandonment of asexual reproduction, there's always an intraspecies selective pressure. And yes performance is a vague issue, but I feel that you're reding my text as if I don't realise this. Birds of paradise are probably the best example of intraspecies pressure producing "performance" that doesn't add up to anything meaningful (except pretty colors) but still the species are stuck in evolving these features as weird choosy females are currently their biggest selective pressure.
 

Does a forced turn over jump over this problem? Actually no, it's the opposite. The only competition that can come once a species is stable like that is from old cohorts competing against young cohorts.
Which is why eventually the top of the food pyramid was taken up by long lived predators like us.
 
You're actually closer to the truth when you're saying it's harder to end up with robust repair mechanisms the bigger (arguably if it's more complex) the organism is. It is harder and there is little selective pressure to achieve it, but once the species is in a stable place in it's environment the selective pressure for longer lives is there.
All long lived species are either apex predators or species which are almost immune to predation - Elephants, whales, big cats, birds, bears.

Which is the opposite of what you're saying! If there was an intrinsic benefit to a high turn over nature would be pushing shorter lifespans on these otherwise quite stable species. It's not.
As a great example - Alligators have remained virtually the same for 200 to 250 million years. Yet can live up to 55 years.

There CAN be a benefit to it. When the species is under pressure to evolve, higher turnover is beneficial. Apex species are not under pressure to evolve.

It's just a question of weather you think the evolution of a species can somehow recognize pressure to evolve - that's what it breaks down to.

Generally, the species that are under high negative selective pressure tend to age faster, have higher turnover rates (and high mutation rates). Even humans when facing scarcity or harsh conditions decrease in mature body size, decrease time to maturity and decrease in mean life span.

Even bacteria, when threatened extinction increase mutation as a response. I found a myriad of genetic stress responses all "directing" evolution to be responsive rather than completely random and arbitrary. And evolution has always "performed" better than expected in a petri dish and that's also because most people, event scientists think its just random.
 

So in my view aging started out as a defect which was not removed because it's a slow process. But as species reach the apex their only competition comes from within the species.

How do you explain that fact that the oldest species evolutionary wise do not age at all and for example all mammals or reptiles age? Hydras, corals and some jelly fish are literally biologically immortal, some crustaceans can live and grow virtually indefinitely. Long lived apex predators on your list are simply long lived, they still reach maturity just as any other animal, stop growing and start ageing, but age slowly.

Species that don't really age, like the ones I listed, do not respect the entire scheme of maturing, stopping growth and so on. Species that age always respect the whole "life cycle" scheme - like your list.
 

At that point the pressure for longer lives is stronger and these species evolve repair mechanisms. There is no aging gene to look for.

And yet, many lifecycle genes are identified, here's a nice one

https://en.wikipedia.org/wiki/FOXO3

"A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[8][9] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms."

And they exist for hundreds of millions of years.

https://en.wikipedia...i/Hydra_(genus)
"Hydra stem cells have a capacity for indefinite self-renewal. The transcription factor, "forkhead box O" (FoxO) has been identified as a critical driver of the continuous self-renewal of Hydra"

Edited by addx, 18 February 2016 - 04:09 PM.

[addx]

And by the way I won't bother looking up how you ended up talking about your evolutionary theories again but please don't mess up the thread. If you want to talk evolution open up another thread.

I got quoted seen what it was about and returned to the forum just because of that, haven't been on in quite a while.

Thanks for the warm welcome :p

[addx]

Anyway what I wanted to express has already been expressed (I just thought of it myself before reading up on it)

https://en.wikipedia...ution_of_ageing

"Ageing theories based on evolvability[edit]
Goldsmith[29] proposed that in addition to increasing the generation rate, and thereby evolution rate, a limited lifespan improves the evolution process by limiting the ability of older individuals to dominate the gene pool. Further, the evolution of characteristics such as intelligence and immunity may specially require a limited lifespan because otherwise acquired characteristics such as experience or exposure to pathogens would tend to override the selection of the beneficial inheritable characteristic. An older and more experienced, but less intelligent animal would have a fitness advantage over a younger, more intelligent animal except for the effects of ageing.

Skulachev[30] has suggested that programmed ageing assists the evolution process by providing a gradually increasing challenge or obstacle to survival and reproduction, and therefore enhancing the selection of beneficial characteristics. In this sense, ageing would act in a manner similar to that of mating rituals that take the form of contests or trials that must be overcome in order to mate (another individually adverse observation). This suggests an advantage of gradual ageing over sudden death as a means of lifespan regulation.

Weissmann's 1889 ageing theory was essentially an evolvability theory. Ageing or otherwise purposely limited lifespan helps evolution by freeing resources for younger, and therefore, presumably better-adapted individuals.

Yang (2013)'s model[2] is also based on mechanisms of evolvability. Aging accelerates the accumulation of novel adaptive genes in local populations. However, Yang changed the terminology of "evolvability" into "genetic creativity" throughout his paper to facilitate the understanding of how aging can have a shorter-term benefit than the word "evolvability" would imply."



And

"Problems with programmed aging theories


Contrary to the theory of programmed death by aging, individuals from a single species usually live much longer in a protected (laboratory, domestic, civilized environment) than in their wild (natural) environment, reaching ages that would be otherwise practically impossible. Also, in majority of species there doesn't exist any critical age after which death rates change dramatically as intended by the programmed death by aging theory, but the age-dependence of death rates is very smooth and monotonic. However, as mentioned above, V.P. Skulachev[33] explained that a process of gradual aging has the advantage of facilitating selection for useful traits by allowing old individuals with a useful trait to live longer. It is also easy to imagine that animals with gradual aging will live longer in a protected environment.
The death rates at extreme old ages start to slow down, which is the opposite of what would be expected if death by aging was programmed. From an individual-selection point of view, having genes that would not result in a programmed death by aging would displace genes that cause programmed death by aging as individuals would produce more offspring in their longer lifespan and they could increase the survival of their offspring by providing longer parental support.[34]"

That's pretty much it, couldn't have said it any better.

[corb]

How do you explain that fact that the oldest species evolutionary wise do not age at all and for example all mammals or reptiles age?

 

Not all of the oldest species are negligibly senescent.
And the inverse is also true, there are negligibly senescent turtles and fish, as well as birds.
Whales are now thought to be negligibly senescent as well. And whales are mammals.

In my view it's down to environment. Some environments are obviously easier to create repair mechanism for - most negligibly senescent animals are aquatic.

Maybe it's not even possible to create perfect mechanisms for some environments through evolution. And since the pressure to do so is weak to begin with it never quite gets there for most multi-cellular life forms. Still some achieve negligible senescence eventually.

A lot of your logic lays on scarcity as a detriment and driver of the evolution of early multi-cellular life, that scarcity did not exist in nature at that point. Or in any point millions of years later, long after aging was already widespread in the biosphere. Incidentally last period of scarcity the biosphere faced a lot of the species that got out of that predicament were either long lived or uni-cellular immortals.

 

Genes which produce increased longevity do exist of course, but that is only natural. In the case of the FOX family, those genes regulate immunity which is important for - removing senescent cells and battling infections and so on. So naturally those increase longevity, but in itself it just proves longevity correlates with enduring external damage.

I'm sure there is a gene which could server your argument better, but it's definitely not that one.

 

 

Contrary to the theory of programmed death by aging, individuals from a single species usually live much longer in a protected (laboratory, domestic, civilized environment) than in their wild (natural) environment, reaching ages that would be otherwise practically impossible. Also, in majority of species there doesn't exist any critical age after which death rates change dramatically as intended by the programmed death by aging theory, but the age-dependence of death rates is very smooth and monotonic. However, as mentioned above, V.P. Skulachev[33] explained that a process of gradual aging has the advantage of facilitating selection for useful traits by allowing old individuals with a useful trait to live longer. It is also easy to imagine that animals with gradual aging will live longer in a protected environment.
The death rates at extreme old ages start to slow down, which is the opposite of what would be expected if death by aging was programmed. From an individual-selection point of view, having genes that would not result in a programmed death by aging would displace genes that cause programmed death by aging as individuals would produce more offspring in their longer lifespan and they could increase the survival of their offspring by providing longer parental support.[34]"

That's pretty much it, couldn't have said it any better.

 

Well that is just the same as saying there is little to no pressure towards longevity after a certain point which is in line with what I'm thinking as well. Naturally if that is the case - and it seems like it is the case - the best way to battle aging, disease and death would be to engineer our own therapies (in contrast to looking for genes in negligibly senescent animals or looking for a "death" clock gene (which most probably doesn't exist)) like we've been doing so far.

Edited by corb, 18 February 2016 - 05:25 PM.

[addx]

 

How do you explain that fact that the oldest species evolutionary wise do not age at all and for example all mammals or reptiles age?

 

Not all of the oldest species are negligibly senescent.
And the inverse is also true, there are negligibly senescent turtles and fish, as well as birds.
Whales are now thought to be negligibly senescent as well. And whales are mammals.

In my view it's down to environment. Some environments are obviously easier to create repair mechanism for - most negligibly senescent animals are aquatic.

Maybe it's not even possible to create perfect mechanisms for some environments through evolution. And since the pressure to do so is weak to begin with it never quite gets there for most multi-cellular life forms. Still some achieve negligible senescence eventually.

A lot of your logic lays on scarcity as a detriment and driver of the evolution of early multi-cellular life, that scarcity did not exist in nature at that point. Or in any point millions of years later, long after aging was already widespread in the biosphere. Incidentally last period of scarcity the biosphere faced a lot of the species that got out of that predicament were either long lived or uni-cellular immortals.

 

Genes which produce increased longevity do exist of course, but that is only natural. In the case of the FOX family, those genes regulate immunity which is important for - removing senescent cells and battling infections and so on. So naturally those increase longevity, but in itself it just proves longevity correlates with enduring external damage.

I'm sure there is a gene which could server your argument better, but it's definitely not that one.

 

 

Contrary to the theory of programmed death by aging, individuals from a single species usually live much longer in a protected (laboratory, domestic, civilized environment) than in their wild (natural) environment, reaching ages that would be otherwise practically impossible. Also, in majority of species there doesn't exist any critical age after which death rates change dramatically as intended by the programmed death by aging theory, but the age-dependence of death rates is very smooth and monotonic. However, as mentioned above, V.P. Skulachev[33] explained that a process of gradual aging has the advantage of facilitating selection for useful traits by allowing old individuals with a useful trait to live longer. It is also easy to imagine that animals with gradual aging will live longer in a protected environment.
The death rates at extreme old ages start to slow down, which is the opposite of what would be expected if death by aging was programmed. From an individual-selection point of view, having genes that would not result in a programmed death by aging would displace genes that cause programmed death by aging as individuals would produce more offspring in their longer lifespan and they could increase the survival of their offspring by providing longer parental support.[34]"

That's pretty much it, couldn't have said it any better.

 

Well that is just the same as saying there is little to no pressure towards longevity after a certain point which is in line with what I'm thinking as well. Naturally if that is the case - and it seems like it is the case - the best way to battle aging, disease and death would be to engineer our own therapies (in contrast to looking for genes in negligibly senescent animals or looking for a "death" clock gene (which most probably doesn't exist)) like we've been doing so far.

 

Im not saying its a single gene. I do think it is quite a complex cascade that eventually shuts down various stem cell activity just as it is a complex cascade that sets them in motion during body development.

Bottom line is, ability for endless self-renewal of cells existed long before multicellularity. I do in fact think a large majority of today cell functions evolved with unicellular lifeforms and most multicellular evolution drew upon that. Stem cells can replace any senescent cell, can they not? They can also divide to dilute any senescence within their lineage. They also in fact do this effectively during the maturing phase (which means the function was never lost!) and "decide" to stop doing it as the body matures.

Proliferation of cells became tightly controlled via these complex cascades in order to build multicellular bodies. As the cells abilities were hijacked for the "greater good" that is the multicellular body, the cell lost ability to self-renew on its own "whim" but now has to follow rules of the "organisation" that is the body. A fruiting body. FOX genes seem to regulate exactly that for exactly those purposes. So do some other more active factors like kappa and mu opioid signalling.

 

During the growth phase, cells are allowed some proliferation, after that, cells are increasingly controlled against self-renewal - which results in ageing of the mature body. Cells want to divide or self-renew by default, something has to keep them from it. Obviously when that something fails - we get cancer cell lineages. As each tissue is controlled by some part of some cascade during development, each tissue probably has a separate mechanism for controlling its proliferation.

In addition to that, there's also the "maturing phase" that alters body building. As the body grows it is also used and from this use the body figures out what to grow more. If you used leg muscles as a kid they will grow stronger and will remain strong for your mature life. If you used your brain for something as a kid, you will have evolved the part of the brain that you used, language, math, music whatever. This is also the difference between maturing and mature.  
Mu and kappa opioid receptors at neuronal stem cells regulate their proliferation or differentiation respectively in response to current events. Mu and kappa opioids are released with success or failure at whatever the nervous system set out to do, meaning success will grow more neurones at the location where it happened (because the neurones at work did something good, so more of them will do more good so that is better), failure will differentiate them more (force them to do more work and less self-repair) and eventually kill them. Mu opioids similarly govern skeletal muscle stem cell proliferation in response to muscle use/pain. This allows you to build muscles by (ab)using them. Opioids are released in most circumstances where something good or bad happened and requires an adaptive response (meaning more good or less bad). 
Point is, when the body becomes mature, it doesn't just start ageing, but halts "adaptive development" described above. Only a few tissues can be adapted in the mature phase like the said muscle tissue. Neurones for example are all grown and done with growing for the most part. 

Furthermore, if you look at these early animals with negligible senescence, they still have preserved asexual reproduction and reproduce sexually when conditions are favorable. It is only with loss of asexual reproduction that ageing as a mechanism really starts to "shine". Thats because what I already stated - sexual reproduction produces a steady slow evolution (while asexual reproduction produces clones), meaning more evolved progeny is expected, not an accident, meaning ageing can be used to enhance the pruneing of the old cohorts faster with a guaranteed beneficial average outcome for the species as whole. It's as simple as that. If the progeny is guaranteed to contain more evolved individuals it is beneficial to prune the old cohorts with the tempo of new progeny reaching maturity (all long lived species that you listed have trouble producing enough progeny that lives to maturity and this matches their longevity. King turtles for example fertilize a whole bunch of eggs, but it takes them decades to reach sexual maturity and they rarely manage to survive to procreate which is why they're on the brink of extinction). 

My thought experiments usually involve scarcity but also slowly or rapidly changing circumstances. Species with fast/high turnover can adapt to shifting circumstances (changing food supply, changing predators, changing climate conditions, changing competition). Populations of immortal species with low turnover get wiped out by any change in circumstances - they're too slow to adapt as a species. Aquatic animals like whales can relocate perhaps to avoid extinction, so can birds...but this just means that the species was "preadapted" to the new circumstances so wasn't forced to adapt - otherwise it would fail. The end result of evolution would be an immortal species that is preadapted to everything life can throw at it, but until then, turnover is required for adaptation to everchanging circumstances in order to avoid extinction.


Where did you read that FOX family regulates immunity? I've not seen a word about it in the wiki articles.

It is quite clearly stated and as predicted: that same genes play a role in embryo development, cellular proliferation and lifespan... they regulate the cell cycle in response to both stress and insulin singalling.. I've not seen a word on immunity...

 

"Some FOX genes are downstream targets of the hedgehog signaling pathway, which plays a role in the development of basal cell carcinomas. Members of the class O regulate metabolism, cellular proliferation, stress tolerance and possibly lifespan. The activity of FoxO is controlled by post-translational modifications, including phosphorylation, acetylation and ubiquitination.^"

 

 

For example the FOXO4 gene reads as follows:

 

https://en.wikipedia.org/wiki/FOXO4

 

"FOXO transcription factors have been shown to be the down downstream effector molecules of insulin-like growth factor (IGF) signaling pathway. In the absence of insulin, PI3K is inactive, so the FOXO homolog daf-16 is able to translocate to the nucleus and turn on many genetic pathways associated with longevity in the roundwormCaenorhabditis elegans.^[14] FOXO’s ability to restrict this pathway produces an increase in lifespan for worms, flies, mice; similar variants of FOXO3a have been associated with longer human lives as well.^[15][16]

Cancer[edit]

Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.^[17][18][19] FOXO4 activates the cell cycle dependent kinase inhibitor, P27, which in turn prevents tumors from progressing into G1.^[20] In HER-2positive tumor cells, increasing FOXO4 activity reduces tumor size.^[20] Chromosomal translocations of FOXO4 have been shown to be a cause of acute leukemia.^[21] The fusion proteins formed by these translocations lack the DNA-binding domain, causing the protein to lose function.^[21]"

 

[addx]

Well that is just the same as saying there is little to no pressure towards longevity after a certain point which is in line with what I'm thinking as well. Naturally if that is the case - and it seems like it is the case - the best way to battle aging, disease and death would be to engineer our own therapies (in contrast to looking for genes in negligibly senescent animals or looking for a "death" clock gene (which most probably doesn't exist)) like we've been doing so far.

 

IMO, I'd much rather look for genes to "reactivate" adolescence  



Here's some interesting stuff, not aligning quite well with some of my predictions but generally showing that lifespan responds to circumstances

 

http://www.encognitive.com/node/3719

 

"Food restriction, the only method shown to extend maximum lifespan and reverse many of the signs of aging in rodents (it is now being looked at in monkeys and humans), provides evidence for the developmental theory of aging. When laboratory rats or mice are severely food-restricted very early in life (right after weaning), they remain small, juvenile, and fail to mature sexually. They also suffer seizures and other severe side effects, in some cases leading to death. The survivors of this highly stringent regime, however, are later (after being put on a normal diet) capable of giving birth to normal offspring at greatly advanced ages, and some of them go on to live extremely long Lifespans...as much as double their normal maximum lifespan!

"

[corb]

Im not saying its a single gene. I do think it is quite a complex cascade that eventually shuts down various stem cell activity just as it is a complex cascade that sets them in motion during body development.

Bottom line is, ability for endless self-renewal of cells existed long before multicellularity. I do in fact think a large majority of today cell functions evolved with unicellular lifeforms and most multicellular evolution drew upon that. Stem cells can replace any senescent cell, can they not? They can also divide to dilute any senescence within their lineage. They also in fact do this effectively during the maturing phase (which means the function was never lost!) and "decide" to stop doing it as the body matures.

 

 

Well let's start with this because this is something I can easily give a definitive answer to.
No. Human stem cells don't have the ability to replace every cell. They are not pluripotent. They lose pluripotency in early embryonic stages. Which is why embryonic stem cells were considered for therapies before the press turned it into a large "ethical" debacle. If a stem cell niche is depleted in the human body it's depleted and that's that.

When you try to promote reprogramming into pluripotency in vivo there is a chance of cancer formation as the result :

http://www.nature.co...icles/srep13559

 

addendum: an interesting tidbit - mice retain pluripotent stem cells for much longer into their development than humans. And yet you get this result in them. I imagine trying the same in humans would be suicide.

 

I am not saying there is no controlled down-regulations of stem cell activity as you age, but all experiments trying to regulate that activity through expression has produced mixed results so far. The closest to controlling those processes with signaling is the parabiosis experiments but in those cases there's more than simple molecules passing through animal to animals by the blood stream. There's antigens, immune cells, blood cells, etc. It's not a simple infusion of signalling molecules and that is why so far no one has been able to replicate those results (which weren't' THAT stellar to begin with) by isolating one or two molecules and supplementing with them alone.

 

 

Species with fast/high turnover can adapt to shifting circumstances (changing food supply, changing predators, changing climate conditions, changing competition). Populations of immortal species with low turnover get wiped out by any change in circumstances - they're too slow to adapt as a species

Most species with negligible senescence have comparable birthrates to their peers.
It's not their lifespan that is important but their ability to procreate when it comes to adaptability.
Considering adaptations happen on the million year scale, and seeing how a few species probably manage to survive more than a hundred or so years because they are killed by other natural sources, aging really doesn't seem like a significant contributor to speed and quality as I pointed out already.

You're making a poor argument for aging with this line of thought really.

 

Now that I think about it, I'm surprised animals like bears can live up to 45 considering they barely manage to live a third of that in the wild. The pressure for lifespan increases through better maintenance in those animals is probably non existent, they can't even reach proper maturity in most cases.

 

 

Where did you read that FOX family regulates immunity? I've not seen a word about it in the wiki articles.

Maybe don't get your info out of wiki articles?

 

http://www.tandfonli...rnalCode=iiri20

Edited by corb, 18 February 2016 - 08:58 PM.

[addx]

This just says it all really... I kept saying fruiting bodies, that's how I see it... and voila:

 

http://www.dailymail...-start-age.html

 

"The results, published in the journal Molecular Cell, claim to pinpoint the start of ageing, disproving the theory that ageing is a slow series of random events.

Researchers studied the transparent roundworm C. elegans, and found this 'switch' is thrown by germline stem cells in early adulthood after it starts to reproduce ensuring its line will live on.

....

All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses
 

"

And that is quite well aligned with everything I'm saying. Sexual reproduction + ageing works in tandem. It is the lifecycle of us as fruiting bodies being turned over in exchange for a steady evolution. This actually provides some rational but also profound sense to the meaning of life, maybe that's why it seems so blasphemous?

[Avatar of Horus]

Here is a recently discovered example of an aging program, in the hair follicle miniorgan, which leads/contributes to its loss:

 

Overview

Quiescent and aging hair follicle stem cells
Stem cells enable normal cell homeostasis, but they also exist in a quiescent state, ready to proliferate and differentiate after tissue damage. Now, two studies reveal features of stem cells in the hair follicle, an epithelial mini-organ of the skin that is responsible for hair growth and recycling (see the Perspective by Chuong and Lei). Wang et al. found that the Foxc1 transcription factor is induced in activated hair follicle stem cells, which in turn promote Nfatc1 and BMP signaling, to reinforce quiescence. Matsumura et al. analyzed hair follicle stem cells during aging. They identified type XVII collagen (COL17A1) as key to hair thinning. DNA damage-induced depletion of COL17A1 triggered cell differentiation resulting in the shedding of epidermal keratinocytes from the skin surface. These changes then caused hair follicle shrinkage and hair loss.

 
the research article:

Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis
Matsumura & Mohri & Binh et al.

Science  05 Feb 2016

Abstract
Hair thinning and loss are prominent aging phenotypes but have an unknown mechanism. We show that hair follicle stem cell (HFSC) aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and in humans. In vivo fate analysis of HFSCs revealed that the DNA damage response in HFSCs causes proteolysis of type XVII collagen (COL17A1/BP180), a critical molecule for HFSC maintenance, to trigger HFSC aging, characterized by the loss of stemness signatures and by epidermal commitment. Aged HFSCs are cyclically eliminated from the skin through terminal epidermal differentiation, thereby causing hair follicle miniaturization. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of COL17A1 in HFSCs, demonstrating that COL17A1 in HFSCs orchestrates the stem cell-centric aging program of the epithelial mini-organ.

 

more info in the structured abstract here:

http://science.scien...51/6273/aad4395

 

[corb]

 

his actually provides some rational but also profound sense to the meaning of life,

Maybe it does to you. Not to everyone.

 

[addx]

 

Im not saying its a single gene. I do think it is quite a complex cascade that eventually shuts down various stem cell activity just as it is a complex cascade that sets them in motion during body development.

Bottom line is, ability for endless self-renewal of cells existed long before multicellularity. I do in fact think a large majority of today cell functions evolved with unicellular lifeforms and most multicellular evolution drew upon that. Stem cells can replace any senescent cell, can they not? They can also divide to dilute any senescence within their lineage. They also in fact do this effectively during the maturing phase (which means the function was never lost!) and "decide" to stop doing it as the body matures.

 

 

Well let's start with this because this is something I can easily give a definitive answer to.
No. Human stem cells don't have the ability to replace every cell. They are not pluripotent. They lose pluripotency in early embryonic stages. Which is why embryonic stem cells were considered for therapies before the press turned it into a large "ethical" debacle. If a stem cell niche is depleted in the human body it's depleted and that's that.

When you try to promote reprogramming into pluripotency in vivo there is a chance of cancer formation as the result :

http://www.nature.co...icles/srep13559

 

addendum: an interesting tidbit - mice retain pluripotent stem cells for much longer into their development than humans. And yet you get this result in them. I imagine trying the same in humans would be suicide.

 

I am not saying there is no controlled down-regulations of stem cell activity as you age, but all experiments trying to regulate that activity through expression has produced mixed results so far. The closest to controlling those processes with signaling is the parabiosis experiments but in those cases there's more than simple molecules passing through animal to animals by the blood stream. There's antigens, immune cells, blood cells, etc. It's not a simple infusion of signalling molecules and that is why so far no one has been able to replicate those results (which weren't' THAT stellar to begin with) by isolating one or two molecules and supplementing with them alone.

 

 

Species with fast/high turnover can adapt to shifting circumstances (changing food supply, changing predators, changing climate conditions, changing competition). Populations of immortal species with low turnover get wiped out by any change in circumstances - they're too slow to adapt as a species

Most species with negligible senescence have comparable birthrates to their peers.
It's not their lifespan that is important but their ability to procreate when it comes to adaptability.
Considering adaptations happen on the million year scale, and seeing how a few species probably manage to survive more than a hundred or so years because they are killed by other natural sources, aging really doesn't seem like a significant contributor to speed and quality as I pointed out already.

You're making a poor argument for aging with this line of thought really.

 

Now that I think about it, I'm surprised animals like bears can live up to 45 considering they barely manage to live a third of that in the wild. The pressure for lifespan increases through better maintenance in those animals is probably non existent, they can't even reach proper maturity in most cases.

 

 

Where did you read that FOX family regulates immunity? I've not seen a word about it in the wiki articles.

Maybe don't get your info out of wiki articles?

 

http://www.tandfonli...rnalCode=iiri20

 

Doesn't matter if they lose pluripotency, there are still stem cell lineages for most tissues if not all that could maintain themselves indefinitely if they "wanted" to.


Maybe you should start with wiki articles.. rather than abstracts...

The family of FOX proteins is responsible for embyonic growth, differentiation and stress response and lifecycle of tissues and longevity. Two proteins quoted in your article out of 30ish in the wiki article have effect on the immune response in some way, but others are responsible for all other tissues... The third protein in your article is researched in your article for effects on beta cells, the protein is related to diabetes type 2/insulin resistance - an old age disease.

Read the link: https://en.wikipedia...ki/FOX_proteins

 

You're way off and completely wrong dismissing the FOX family of proteins with a comment that they're not even a good candidate as they only regulate the immune response or whatever you said... 

 

 

Ill try and link this google book which literally states FOXO subgroup of the FOX proteins inhibit senescence in organisms from yeast to mice... it also states that FOXO subgroup regulates cell oxidative stress response, cell heat stress response, cell shear stress response, cell inflammatory response and tissue development and life cycle and so on and so on..

 

 https://books.google...lerance&f=false

Edited by addx, 18 February 2016 - 10:09 PM.

[corb]

Doesn't matter if they lose pluripotency, there are still stem cell lineages for most tissues if not all that could maintain themselves indefinitely if they "wanted" to.

 

You have to remember even uni-cellulars "age" under stress. There's no such thing as a truly immortal cell. They just don't age under certain conditions. We've inherited a lot of mechanisms from them sure but it's not like they are completely applicable for multi-cellular life.

 

When labs immortalize human stem cell lines they do it with hTERT.
As it happens we'll be getting in vivo results from a therapy that induces that in humans sooner rather than later, so MAYBE we could lay that one to rest once and for all.

 

Edited by corb, 18 February 2016 - 10:27 PM.

[addx]

http://www.ncbi.nlm....les/PMC3295030/

 

"It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. 

 

The IIS system is an ancient system that is highly conserved and coordinates growth, differentiation and metabolism in response to changing environmental conditions and nutrient availability

"...

[corb]

http://www.ncbi.nlm....les/PMC3295030/

 

"It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. 

 

The IIS system is an ancient system that is highly conserved and coordinates growth, differentiation and metabolism in response to changing environmental conditions and nutrient availability

"...

 

Maybe you should consider that all the papers you've been posting so far we've seen.
And dismissed. Because they've received counterarguments.

 

http://www.ncbi.nlm....pubmed/23873963

 

 

he results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

[addx]

 

http://www.ncbi.nlm....les/PMC3295030/

 

"It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. 

 

The IIS system is an ancient system that is highly conserved and coordinates growth, differentiation and metabolism in response to changing environmental conditions and nutrient availability

"...

 

Maybe you should consider that all the papers you've been posting so far we've seen.
And dismissed. Because they've received counterarguments.

 

http://www.ncbi.nlm....pubmed/23873963

 

 

he results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

 

Yes, but I was really quoting it for the general idea of having longevity in a feedback loop with insulin and the relatedness of the mechanism to FOXO proteins 

 

"Variants in FOXO3A have been associated with longevity in an ethnic Japanese population in Hawaii [48], as well as in four different Caucasian cohorts [47,49,50] and in a Chinese cohort
...

To date, although only few findings have been systematically replicated in different cohorts and confirmed in meta-analyses, these data seem to indicate that of the single genes of the IIS pathway that have been systematically analyzed across different cohorts, variation in FOXO3A is most consistently associated with human longevity [1].

...
The mechanisms through which a low insulin drive with enhanced FoxO activation may contribute to longevity include a metabolic shift from glucose to lipid oxidation, with concomitant enhancement of cellular stress resistance and protection, suppression of inflammation and enhanced mitochondrial biogenesis "


 

[corb]

 

 

http://www.ncbi.nlm....les/PMC3295030/

 

"It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. 

 

The IIS system is an ancient system that is highly conserved and coordinates growth, differentiation and metabolism in response to changing environmental conditions and nutrient availability

"...

 

Maybe you should consider that all the papers you've been posting so far we've seen.
And dismissed. Because they've received counterarguments.

 

http://www.ncbi.nlm....pubmed/23873963

 

 

he results are consistent with a significant role for IGF-1 in the modulation of life span but contrast with the published life-span data for the hypopituitary Ames and Snell dwarf mice and growth hormone receptor null mice, indicating that a reduction in IGF-1 alone is insufficient to increase both mean and maximal life span in mice.

 

Yes, but I was really quoting it for the general idea of having longevity in a feedback loop with insulin and the relatedness of the mechanism to FOXO proteins 

Longevity is one thing. If we're talking general longevity I can agree with you.

There's "recent" hits like GDF8, and INK4, and AKT1 (which I guess relates well with IFG1), etc. there are mutants that don't have those in certain human populations. There is a small list of genes which when inhibited or activated could give you a couple years extra and bit of extra health to go with it I suppose. But even in animal studies they don't produce that impressive of a result.