26 replies to this topic

[solbanger]

Researchers at Northwestern University found that the aging process began in c.elegans worms upon reaching sexual maturity. They noted that heat shock response diminished in sexually mature worms indicating that certain stress protective pathways were turned off. The researchers found that it was the germline cells controlling sperm and eggs that controlled the switch.

 

So it seems that most organisms come with a preplanned expiration date!

 

http://www.northwest...in-animals.html

 

[mpe]

Sorta blows random damage out the window.

[Saintless]

Very interesting, I wonder if these explains the apparent lifespan boosts in :

 

neutered cats and dogs live much longer receiving an 18%+62% boost in lifespan

 

http://www.banfield....e-to-longer-lif

 

Theres also information about Eunuchs castrated as boys living much longer 10-20 years.

 

In plants I've noticed when you don't allow a flowering plant to go to seed (by cutting them) they live much longer and are usually much healthier.

 

 

[corb]

Can't wait for the same scientist to talk about "post aging syndrome" in a decade just like the mTOR church.

Quality control overdrive gets down-regulated about the same time rapid growth stops? What a surprising discovery!

You people never learn.

 

I'd be surprised if anything worthwhile for longevity comes of this. Now that would be a real surprise.

Oh and furthermore - the lifespan of c.elegans is about two weeks in length. So where's the lifespan study? It would've taken a couple of days to confirm.

 

All of these articles about genes affecting lifespans are always such a giggle.

Edited by corb, 24 July 2015 - 07:45 AM.

[Mind]

Sorta blows random damage out the window.

 

If it was the case that aging was completely programmed, one would think the hormone replacement therapy would completely stop or reverse the aging process, right? It doesn't. So you would think there would be more to aging than just flipping a simple switch (or switches)

[Avatar of Horus]

Same topic subject here:
Arguing that Heat Shock Response Decline is Programmed
http://www.longecity...-is-programmed/

[mpe]

 

Sorta blows random damage out the window.

 

If it was the case that aging was completely programmed, one would think the hormone replacement therapy would completely stop or reverse the aging process, right? It doesn't. So you would think there would be more to aging than just flipping a simple switch (or switches)

 

 

HRT doesnt stop or reverse aging because it deals with symptoms not causes. Those symptoms can be pretty horrible and yes they can kill you.

 

If the "switch being flipped" is upstream of the observable change wouldn't flipping it back off or on improve the situation, even if it only prevented a further degradation of the symptoms if its caught early enough.

 

If its not reversed soon enough it wouldn't matter what the cause was or how it occurred; a bit like seeing the petrol cans around the house that's burning to the ground.Yes that's the SENS mantra, but SENS wont help if you don't fix the underlying cause. SENS is about replacing the hormones and tissues without fixing the underlying cause. That's like trying to rebuild a house while its still on fire, rebuilding it wont put out the fire.

 

Now, maybe we do know one of the underlying causes, and its not random.

 

 

.Mike

[solbanger]

Hi guys,

 

I posted this topic and it did get me thinking. This might only be one part of the puzzle. True aging may be a multitude of factors working at the same time. Addressing one piece of it is nice but doesnt stop the other factors. For instance telomere reduction still takes place in organisms whether heat shock response is turned on or off so an aspect of aging still does occur. This would let eunichs and deflowered plants to live longer yes but eventually die of all the other epigenetic affects.

 

So although these researchers discovered a pathway to reduce stress in mature organisms, it still doesn't address telomere shortening, the buildup of pollutants and waste in the body, the evolution and increased lethality of pathogens or cancer susceptibility. These additional features, which I believe are part of the SENS model, should be addressed as well in our total picture of the aging process.

[HighDesertWizard]

Some fundamental biological substances, organs, and functions important in morbidity, mortality, and longevity in Wild-Type Humans have already been identified. Thousands of studies have been written about the details of these biological independent variable nodes and we have various kinds of longitudinal studies, including some significant graphical Survival Curves indicating their importance in Humans...

 

And I mean, specifically, NF-kB Inhibition and longer Telomere Length. And it turns out, biological processes concerned with Telomerase and NF-kB are biologically intimate, though all the details are unknown. I believe NF-kB and Telomere related processes are at the core of a larger, multi-organ, multi-substance, and multi-process mechanism...

 

The point is to figure out where the key intervention points that can positively impact Longevity might be...

 

It's preposterous that scientists allow their study findings to be presented by media managers as providing some heretofore unknown aging switch. We know it's more complicated than that. IMO, when these sorts of findings are published, it's a simple thing for us to ask...

 

How does this study finding relate to what we already know to be important in Wild-Type Humans?

 

Forget about the Magic Switch idea... Focus on the biological function highlighted in the study as being important, in this case, that's the loss of Heat Shock Response... Now let's ask the question... What does the Heat Shock Response have to do with what we already know is important in Wild-Type Humans... I always start with the relationship to NF-kB and I fall back to look for TNF, IL-1, and/or IL-6....

 

I call this approach to accumulating knowledge about Longevity... NF-kB Pingpong... I start with what we already know to be important in Wild-Type Humans...

 

If decline in the Heat Shock Response is associated with aging then my hypothesis is that I'm going to be able to find a study showing that HSR modulates NF-kB in some direct or indirect way...

 

I don't always get a hit, but I always learn something... In this case, the answer comes fast with a page 1 google scholar hit... Many relevant study returns including this one from 2005 that confirms that the NF-kB related hypothesis is true... No need to paste in the abstract, the study title says it all...

 

Heat Shock Inhibits NF-kB Activation in a Dose- and Time-Dependent Manner

Edited by HighDesertWizard, 26 July 2015 - 07:39 PM.

[treonsverdery]

 Apprciate the article

among the longevity possibilities are using gene therapy on [similar to postpubertal] c elegans to find out if they then live longer.  Other possibilities are cyproterone acetate or possibly research on what dafachronic acids (like c elegans sex hormones) do at humans.

 

The source paper notes a histone gene.  this is what epigenie describes about  that histone gene  H3K27 is known for one thing: shutting down transcription. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters. It acts in opposition to H3K4me3. Because of its dramatic and predictable effect on gene expression, H3K27me3 is a favorite of epigenetic researchers looking for inactive genes. Most histone methylations are catalyzed by many enzymes. H3K27me3 is distinct in that it has only one known methyltransferase: EZH2 (Kuzmichev et al., 2002). EZH2 is part of the PRC2 complex which is responsible for the repression many genes involved in development and cell differentiation (Boyer et al., 2006; Bracken et al., 2006). It is thus believed that H3K27me3 is critical for the repression of developmental genes. H3K27me3 is also an important mark of the inactive X chromosome (Xi) (Rougeulle et al., 2004).

http://epigenie.com/.../histone-h3k27/

 

 

 

 

Here is a description of the Northwestern University paper Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction.

Labbadia J1, Morimoto RI2.

Author information

 

Abstract

The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. The removal of germline stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci, and maintains the HSR. These findings suggest that competing requirements of the germline and soma dictate organismal stress resistance as animals begin reproduction.

Copyright © 2015 Elsevier Inc. All rights reserved.

PMID: I     26212459        

 

So, among humans then it is possible that as a longevity drug with noted effects on sex drive could be dafachronic acid 

Steroid hormones controlling the life cycle of the nematode Caenorhabditis elegans: stereoselective synthesis and biology.

Martin R1, Entchev EV, Kurzchalia TV, Knölker HJ.

Author information

 

Abstract

Cholesterol-derived hormones, the dafachronic acids, play a major role in controlling the life cycle and initiating dauer larva formation of the nematode Caenorhabditis elegans. This Perspective describes recent progress in the synthesis of these steroid hormones and their biological function.

 

Edited by treonsverdery, 19 August 2015 - 06:58 PM.

[Avatar of Horus]

 Apprciate the article

among the longevity possibilities are using gene therapy on [similar to postpubertal] c elegans to find out if they then live longer.  Other possibilities are cyproterone acetate or possibly research on what dafachronic acids (like c elegans sex hormones) do at humans.

 

The source paper notes a histone gene.  this is what epigenie describes about  that histone gene  H3K27 is known for one thing: shutting down transcription. When H3K27 is trimethylated, it is tightly associated with inactive gene promoters. It acts in opposition to H3K4me3. Because of its dramatic and predictable effect on gene expression, H3K27me3 is a favorite of epigenetic researchers looking for inactive genes. Most histone methylations are catalyzed by many enzymes. H3K27me3 is distinct in that it has only one known methyltransferase: EZH2 (Kuzmichev et al., 2002). EZH2 is part of the PRC2 complex which is responsible for the repression many genes involved in development and cell differentiation (Boyer et al., 2006; Bracken et al., 2006). It is thus believed that H3K27me3 is critical for the repression of developmental genes. H3K27me3 is also an important mark of the inactive X chromosome (Xi) (Rougeulle et al., 2004).

http://epigenie.com/.../histone-h3k27/

 

 

Here is a description of the Northwestern University paper Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction.

Labbadia J1, Morimoto RI2.

Author information

 

Abstract

The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. The removal of germline stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci, and maintains the HSR. These findings suggest that competing requirements of the germline and soma dictate organismal stress resistance as animals begin reproduction.

Copyright © 2015 Elsevier Inc. All rights reserved.

PMID: I     26212459        

 

...

 

This recent article of this topic seems to be connected, as it mentions those epigenetic markers too:

Another Example of Rejuvenation of Cell Characteristics through Induced Pluripotency - BioscienceNews - LONGECITY -21 Jul 2015

http://www.longecity...d-pluripotency/

[albedo]

There is a very interesting and recent article by Dr Aubrey de Grey (June 2015) about his rebuttal of a programmed aging leaving SENS strategy as a more realistic one. I report the abstract (bold is mine)

 

Do We Have Genes that Exist to Hasten Aging? New Data, New Arguments, But the Answer is Still No

Article in Current Aging Science 8(1) · June 2015

DOI: 10.2174/1874609808666150421131304

 

Abstract

In the 60 years since Medawar questioned the assumption that aging is a selected trait with a fitness benefit, mainstream biogerontology has overwhelmingly adopted the view that aging is a product of evolutionary neglect rather than evolutionary intent. Recently, however, this question has come to merit further scrutiny, for three reasons: a variety of new ways in which aging could indeed be “programmed” have been proposed, several phenomena with superficial similarities to programmed aging have been suggested to offer evidence for it and against the mainstream consensus, and above all it has become appreciated that the existence or otherwise of “pro-aging genes” has enormous implications for determining our optimal strategy for the medical postponement of age-related ill-health. Accordingly, it is timely to revisit the arguments and data on this topic. In this article I discuss difficulties in reconciling the programmed-aging concept with existing data, flaws in various arguments given by others that existing data prove aging to be programmed, and extensions of these considerations to various phenomena that in one or another way resemble programmed aging. I conclude that, however much we might wish that aging were programmed and thus that the ill-health of old age could be greatly postponed just by disabling some aspect of our genetic makeup, the unfortunate truth is that no such program exists, and thus that our only option for substantial extension of healthspan is a divide-and-conquer panel of interventions to repair the damage that the body inflicts upon itself throughout life as side-effects of its normal operation. I explicitly avoid arguments that rely on unnecessarily abstruse evolutionary theory, in order to render my line of reasoning accessible to the broadest possible audience.

 

[niner]

In case people think that de Grey's paper that albedo posted above is biased by his own research agenda, here is another paper from the same issue:
 

Physiological and Comparative Evidence Fails to Confirm an Adaptive Role for Aging in Evolution
Current Aging Science, 8(1): 14-23.
Alan A Cohen.

Affiliation: Groupe de recherche PRIMUS, Department of Family Medicine, University of Sherbrooke, 3001 12e Ave, N, Sherbrooke, QC, J1H 5N4, Canada.

The longstanding debate about whether aging may have evolved for some adaptive reason is generally considered to pit evolutionary theory against empirical observations consistent with aging as a programmed aspect of organismal biology, in particular conserved aging genes. Here I argue that the empirical evidence on aging mechanisms does not support a view of aging as a programmed phenomenon, but rather supports a view of aging as the dysregulation of complex networks that maintain organismal homeostasis. The appearance of programming is due largely to the inadvertent activation of existing pathways during the process of dysregulation. It is argued that aging differs markedly from known programmed biological phenomena such as apoptosis in that it is (a) very heterogeneous in how it proceeds, and (b) much slower than it would need to be. Furthermore, the taxonomic distribution of aging across species does not support any proposed adaptive theories of aging, which would predict that aging rate would vary on a finer taxonomic scale depending on factors such as population density. Thus, while there are problems with the longstanding non-adaptive paradigm, current evidence does not support the notion that aging is programmed or that it may have evolved for adaptive reasons.

 

Edited by niner, 25 August 2015 - 11:17 PM.

[Avatar of Horus]

There is a very interesting and recent article by Dr Aubrey de Grey (June 2015) about his rebuttal of a programmed aging leaving SENS strategy as a more realistic one. I report the abstract (bold is mine)

 

Do We Have Genes that Exist to Hasten Aging? New Data, New Arguments, But the Answer is Still No

Article in Current Aging Science 8(1) · June 2015

DOI: 10.2174/1874609808666150421131304

 

Abstract

... I conclude that, however much we might wish that aging were programmed and thus that the ill-health of old age could be greatly postponed just by disabling some aspect of our genetic makeup, the unfortunate truth is that no such program exists, ...

 

 

What about, for instance, the insulin-like growth factor 1 gene then?

 

Btw the two articles differ, the link and the abstract.

Edited by Avatar of Horus, 25 August 2015 - 10:22 PM.

[niner]

Btw the two articles differ, the link and the abstract.

 

Here's the link to the issue.

[nowayout]

 

Sorta blows random damage out the window.

 

If it was the case that aging was completely programmed, one would think the hormone replacement therapy would completely stop or reverse the aging process, right? It doesn't. So you would think there would be more to aging than just flipping a simple switch (or switches)

 

 

Well, which hormones?  The paper mentions some molecular signaling, but I don't think they are talking about the testosterone or estrogen used in human HRT, so I don't follow why conventional HRT should reverse aging even if they are right, or why the failure of conventional HRT should prove them wrong. 

Edited by nowayout, 25 August 2015 - 11:38 PM.

[albedo]

 

What about, for instance, the insulin-like growth factor 1 gene then?

 

Btw the two articles differ, the link and the abstract.

 

 

Thank you (and niner) for having detected the problem and reposted the link. Here is the one I wished to link :

http://www.ncbi.nlm....pubmed/25902458

 

IFG-1? I believe it is still controversial and read IGF-1 role is confounded by many endocrine deficiencies happening during ageing:

http://www.sciencedi...168952502026963

 

I wonder if you have comments on your personal IGF-1 level trend. I am 60 and have it constant since ~10 years at about 25 nmol/l (or 191 mcg/l) with respect to ref. range 4.6-25.6 (or 35-195)

                   

 

Edited by albedo, 26 August 2015 - 09:20 AM.

[albedo]

In addition to my and niner's last post above, there are also theoretical considerations on the dynamics of genes regulating the aging process that seems pointing to a convergence between random variations, which I expect underlying the functional and repair mechanism degradation (where SENS is likely the only realistic approach), and programmed aging. So maybe conflicting approaches will one day converge, the latter also adding to the motivation and necessary of a dramatic increase of aging research funding, now only few % of health related budget research, i.e. including SENS as well all the other approaches.

 

See for example (fully text):

http://arxiv.org/abs/1502.04307

".... We show that ageing contains both a stochastic component, related to regulatory error accumulation in transcription/translation/metabolic pathways, and a strong deterministic component, which can be naturally associated with a part of a development programme. We conclude on this basis that two opposing hypotheses of ageing, error accumulation and programmed ageing are in fact compatible...."

 

[Avatar of Horus]

There is a very interesting and recent article by Dr Aubrey de Grey (June 2015) about his rebuttal of a programmed aging leaving SENS strategy as a more realistic one. I report the abstract (bold is mine)
 
Do We Have Genes that Exist to Hasten Aging? New Data, New Arguments, But the Answer is Still No
Article in Current Aging Science 8(1) · June 2015
DOI: 10.2174/1874609808666150421131304
 
Abstract
... I conclude that, however much we might wish that aging were programmed and thus that the ill-health of old age could be greatly postponed just by disabling some aspect of our genetic makeup, the unfortunate truth is that no such program exists, ...

 
What about, for instance, the insulin-like growth factor 1 gene then?
 
Btw the two articles differ, the link and the abstract.

 

What about, for instance, the insulin-like growth factor 1 gene then?
 
Btw the two articles differ, the link and the abstract.

 
Thank you (and niner) for having detected the problem and reposted the link. Here is the one I wished to link :
http://www.ncbi.nlm....pubmed/25902458
 
IFG-1? I believe it is still controversial and read IGF-1 role is confounded by many endocrine deficiencies happening during ageing:
http://www.sciencedi...168952502026963
...

 
Yes it is still controversial, but what I meant is like these:
 

Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice?
Piper et al. 2008
http://www.ncbi.nlm....pubmed/18226095

Abstract
Ageing research has been revolutionized by the use of model organisms to discover genetic alterations that can extend lifespan. In the last 5 years alone, it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce. Here, we summarize the body of work that has lead to these discoveries and point out areas of interest for future work in characterizing the genetic, molecular and biochemical details of the mechanisms to achieving a longer and healthier life.

 
another one:

Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice
Selman et al. 2008
http://www.ncbi.nlm....pubmed/17928362

Abstract
Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1-/- mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1-/- female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2-/- mice were short-lived, whereas Irs1+/- and Irs2+/- mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.

 
But I will make another post to clarify some of the mentioned programmed aging things.
 

I wonder if you have comments on your personal IGF-1 level trend. I am 60 and have it constant since ~10 years at about 25 nmol/l (or 191 mcg/l) with respect to ref. range 4.6-25.6 (or 35-195)

I don't have comments on this, I am still in examination phase on IGF-1 in my research.

[Avatar of Horus]

another example/description on IGF1:

... the insulin/IGF signaling, and related to the - btw Mprize record holder - so-called dwarf mice phenomenon, specifically the Ames type, its description:

Primordial follicle activation in the ovary of Ames dwarf mice
Schneider et al. 2014
http://www.ncbi.nlm....pubmed/25543533
...
The Ames dwarf mice (df/df) carry a mutation at the Prop1 (Prophet of Pit1) locus that impairs the development of the anterior pituitary gland [1], resulting in deficiency of growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin [2]. As the result of the GH deficiency these mice are characterized by severely low circulating insulin-like growth factor I (IGF-I) and reduced adult body size [3]. Importantly, regardless of these hormonal deficiencies, df/df mice live 35-75% longer than their normal littermates [4]. ...

 
In the following paper the researchers investigated the possibly underlying life extension mechanism:
"Furthermore, increased longevity due to decreased GH or IGF-1 signaling led us to investigate the post-transcriptional regulation of genes involved in this desired phenotype-the delayed onset of aging-while bypassing undesirable effects associated with these hormonal deficiencies (e.g., reduced size, impaired reproductive capacity, etc.).",
...:

MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging
Bates et al. 2009
http://www.ncbi.nlm....pubmed/19878148
Abstract
The Ames dwarf mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the post-transcriptional regulation of gene expression and its impact on longevity remains to be explored.

... compared to its normal siblings, the dwarf mouse exhibits a head start in regulating these pathways to control their normality, which may ultimately contribute to its extended health-span and longevity.

 
...

 

[Avatar of Horus]

 

There is a very interesting and recent article by Dr Aubrey de Grey (June 2015) about his rebuttal of a programmed aging leaving SENS strategy as a more realistic one. I report the abstract (bold is mine)
 
Do We Have Genes that Exist to Hasten Aging? New Data, New Arguments, But the Answer is Still No
Article in Current Aging Science 8(1) · June 2015
DOI: 10.2174/1874609808666150421131304
 
Abstract
... I conclude that, however much we might wish that aging were programmed and thus that the ill-health of old age could be greatly postponed just by disabling some aspect of our genetic makeup, the unfortunate truth is that no such program exists, ...

 
...
But I will make another post to clarify some of the mentioned programmed aging things.

 

 

So here is Dr. de Grey's definition of the programmed aging, from his above paper, available at the link niner shared above:

INTRODUCTION
Much of the debate concerning whether aging is programmed
has, as so often in science, suffered from mutual
misunderstanding about what is really being debated. It is
thus appropriate to begin with some precise definitions of
terms. In this paper, the following definitions will be used:

...

Programmed aging theory (PA): the contention
that aging in most metazoans occurs mainly due
to the action of genetic pathways whose selected
function is to accelerate that accumulation and
thereby hasten decline and death, without any compensating
individual evolutionary fitness benefit, only
non-individual benefit, and that species differences in
the rate of aging arise mainly from differences in the
strength of these “pro-aging” pathways.

 
Non-programmed aging theory (NPA): the
contention that aging in most metazoans occurs entirely
due to imperfections (gaps) in the organism’s
genetically-programmed pro-homeostatic arsenal persists
because selection exerts insufficient pressure to
drive the evolution of greater comprehensiveness of
that arsenal, and that species differences in the rate of
aging arise solely from differences in that selective
pressure, which arise in turn from differences in risk
of death from extrinsic causes such as predation.

...

 

What I wanted to say is that this however is just a subtype of the programmed aging theory, the self-destructive, or programmed organism death, from the programmed cell death.

Some scholars maintain this, eg.:

Josh Mitteldorf has an interesting blog where he sometimes gets on this subject. He is on the programmed aging side of things.
 

Most people misunderstand what aging is. It’s not just the public who have been deceived — Most scientists and medical researchers who study aging are on the wrong track.
The culprit is the “natural medicine” movement that has dominated thinking about our bodies for the last 50 years. “Respect the body’s wisdom. Work with the body to fix what has gone wrong.” This approach has worked so well with injuries and many diseases that it is understandable that people want to extend it to aging as well.
Diseases of aging have been treated as if they were something that goes wrong, something we have to help the body to fix. But in fact, the evidence accumulating in recent decades is that aging is not something that goes wrong, and the body is not trying to fix it. Aging is natural. It is the body shutting itself down, putting itself out of the way after it has done its job, finished reproduction.

What is Aging? Most Scientists Still Get it Wrong
http://joshmitteldor...l-get-it-wrong/

 

the continuation of the above Mitteldorf quote is this:

"How do we know that aging is an active process of self-destruction, and not just the body “wearing out”?  There are a number of indications, becoming clearer all the time.

..."

 

But there is the another subtype of the PA theory, which states that aging is the consequence of the changes in the endogenous processes, governed by the genetic code, which becomes deregulated with age, and this causes the dysfunctions. The purposeless continuation of the developmental program, i.e. evolutionary it was not selected for or against. Note: I mean within the given species, because in family and genus it may have, like e.g. in the evolution of Homo sapiens, as its lifespan has doubled from its predecessors in just a course of a few million years, with relatively few genetical changes, around 3-5%, i.e. in about 1000-1500 genes.

 

A description of it is given, for instance, here, by Joao Pedro de Magalhaes:

http://www.senescenc...s_of_aging.html

"I should note that there are differences in interpretation of aging changes which influence the way different researchers interpret the essence of aging; as discussed elsewhere, some authors see aging as genetic in nature while others see it as a build-up of damage counteracted by genetically-regulated mechanisms."

 

http://www.senescenc...mmed_aging.html

"Programmed Theories of Aging

 

In addition to damage-based theories, a second class of theories of aging defends that aging is a genetically-determined, programmed process. In this essay, I present and review the most important concepts and theories in this context.

...

For decades the idea that aging is programmed has been debated, and it was given new impetus by the extraordinary discoveries in the genetics of aging. The observation that single genes can modulate longevity and, to some degree, regulate the process of aging in model systems supports the idea that aging is to some degree programmed. For example, in yeast, transient expression of a single transcription factor can rejuvenate cells and extend lifespan (Unal et al., 2011). Of course, the same may not hold true for more complex organisms, like vertebrates, and discussed below are some of the proposed models of aging based on the concept of programmed aging.

Though there have been arguments in favor of seeing aging as part of an altruistic predetermined plan that serves a purpose (Longo et al., 2005), the idea that aging evolved for a reason--also known as group selection--is largely out-of-favor in modern gerontology. As mentioned elsewhere, in the vast majority of species, aging does not appear to be programmed in the sense that it serves a purpose (Austad, 2004). Therefore, in this essay, I do not imply any evolutionary purpose for aging; by programmed I mean in the sense of following a predetermined set of instructions, like in the result of gene action.

...

 

 

 

Anyway, in the other topic of this subject (linked in post #6,  http://www.longecity...ndpost&p=737649), I already wanted to suggest the creation at Longecity of a Frequently Asked Questions article, let's say:

Aging and Life extension FAQ,
that describes the definitions of the basic concepts connected to these. For without such definitions, reasoning and arguments cannot be built up properly, and because it seems there may be some misunderstandings in the definitions too between various people and groups.
I will probably post it in the Project Ideas section soon.

 

[corb]

in the sense of following a predetermined set of instructions, like in the result of gene action

 

Isn't this just a roundabout way of saying antagonistic pleiotropy?

[Avatar of Horus]

 

in the sense of following a predetermined set of instructions, like in the result of gene action

 

Isn't this just a roundabout way of saying antagonistic pleiotropy?

 

 

I think it's more like to a simple but overall genetic deregulation, independently of the functions of the given genes. BTW the presented IGF-1 thing can be considered as an example of antagonistic pleiotropy.

Under the morphogenetic, developmental phase, the expression of the genes, and thus the molecular, protein composition of a given body, is tightly regulated. So the logic behind the theory is that in aging this becomes unbalanced, and when this happens, the cells, tissues and organs cannot function properly and disorders develop, and after a while the whole thing falls apart and eventually collapses.
And if the genetic regulation issue is corrected it results in functional preservation/restoration.

Several examples, that belongs to this category, can be given:
I have already presented some in other topics:
the thymus and FOXN1:
http://www.longecity...ndpost&p=728834

the liver/lysosomes and LAMP2:
http://www.longecity...ndpost&p=706435

 

the heart and CD36:
Study: Fountain of youth for your heart?
University of Alberta, 2-Nov-2007
http://www.eurekaler...a-sfo110207.php

CD36 expression contributes to age-induced cardiomyopathy in mice
Koonen DP1, Febbraio M, Bonnet S, Nagendran J, Young ME, Michelakis ED, Dyck JR.
Circulation. 2007 Nov 6;116(19):2139-47. Epub 2007 Oct 22.
http://www.ncbi.nlm....pubmed/17967771


BTW there is a recent paper that discusses this in a general sense, and it concludes that, examining various species, there is a correlation between the gene expression stability and longevity/lifespan:
"We conjectured, therefore, that the lifelong transcriptional stability of an organism may be a key determinant of longevity."

"These scientists noticed that in long-lived animals, negligible senescence is accompanied by exceptionally stable gene expression."

It has two topics in the BioscienceNews section:
Theorizing on Gene Network Stability and Aging
http://www.longecity...lity-and-aging/

Steadier Gene Networks Mean Longer Lifespans
http://www.longecity...nger-lifespans/
 

Edited by Avatar of Horus, 30 August 2015 - 07:10 AM.

[TheLifeScience]

Very interesting, I wonder if these explains the apparent lifespan boosts in :

 

neutered cats and dogs live much longer receiving an 18%+62% boost in lifespan

 

http://www.banfield....e-to-longer-lif

 

Theres also information about Eunuchs castrated as boys living much longer 10-20 years.

 

In plants I've noticed when you don't allow a flowering plant to go to seed (by cutting them) they live much longer and are usually much healthier.

 

Wait, so not jerking off could potentially extend my life? Tough decisions...

 

But needing no spermatogenesis (including precursor hormones - GnRH) could have something to do with it.

Edited by TheLifeScience, 07 September 2015 - 10:34 PM.

[Gern]

I think the broader theory proposed by the paper differs from Aubrey de Greys definition. It is that the genes involved in sexual maturity also turn off specific genetic pathways involved in mitochondrial aging. If those pathways are involved in genetic repair then that would be three theories of aging all tied up neatly in one explanation.

Too many scientists don't understand root cause analysis. It seems unlikely (or at least a violation of Occams Razor) to suggest aging is due to a host of mechanisms all of which just happen to start around the same time. In a system as complex as the human body it is far far to easy to confuse cause with root cause. As long as you can look at any theory of aging and reasonably ask "but why does that happen." Then you haven't found the root cause. This is the problem with most theories of aging. They explain some aspect but leave questions like "ok but what causes that to occur," or "why does this process not start at age thee or thirteen or twenty," or "why are reproductive cells immune to that effect." If those questions blow up your theory then you probably haven't found the root cause.

[albedo]

This recent and well done study adds to the subject matter:

 

Mcdaid AF, Joshi PK, Porcu E, et al. Bayesian association scan reveals loci associated with human lifespan and linked biomarkers. Nat Commun. 2017;8:15842.

https://www.nature.c...les/ncomms15842

 

 16 LS SNPs EPFL.PNG   803.82KB   1 downloads

 

"The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan."

 

 

[Gern]

it seems obvious to me that aging starts at conception. The list of physical and cognitive changes a human goes through before reaching maturity is huge and nearly always follows a set path. The changes a body goes through as they age is huge and nearly always seems to follow a set path. The idea that the the changes that occur prior to maturity and the changes that occur after are due to different root causes seems unlikely to me. Just looking at it from the 10,000 foot view with no science to back it up.