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- Progress Isn't Fast Enough, But Betting Against Radical Life Extension this Century Still Seems Foolish
- Arguing for Cellular Senescence to Emerge from Distinct Underlying Stress Response Modules
- A Comparison of Calorie Restriction and Intermittent Fasting in Genetically Diverse Mice
- Implanting Senescent Cells into the Skin of Mice Accelerates Multiple Age-Related Declines
- Yet Another Study of Age-Related Changes Taking Place in the Gut Microbiome
- Exploring Causal Relationships Between Epigenetic Age and Neurodegenerative Disease
- Immune Cells that Prevent Metastatic Cancer Cells from Proliferating After Migration
- Demonstrating Glymphatic Drainage of Cerebrospinal Fluid in Humans
- A Metabolomic Profile of Aging Derived from a Large Data Set
- Reviewing What is Known of the Role of the Gut Microbiome in Aging
- Investigating the Age-Related Decline of Choroid Plexus Function
- Senescent Microglia are Likely Important in Age-Related Neurodegeneration
- More Selective Disruption of Growth Hormone Metabolism in Mice Still Extends Life
- Upregulation of aal1 Long Non-Coding RNA Extends Life in Flies
- Characterizing Senescent Cell Burden in Skin
Progress Isn't Fast Enough, But Betting Against Radical Life Extension this Century Still Seems Foolish
https://www.fightaging.org/archives/2024/10/progress-isnt-fast-enough-but-betting-against-radical-life-extension-this-century-still-seems-foolish/
Progress in medicine is painfully slow, in part thanks to the perverse incentives that drag down every heavily regulated field. But seven decades are left before we reach the closing years of this century. Seventy years in medicine is a long time. Consider what the medical science of the 1950s looked like in practice; consider what the treatment options looked like for common age-related diseases in that era, where they existed at all. Given that a longevity industry is just getting started, barely a decade old at this point, it seems a strange idea to bet against sizable gains in human life span before the end of the century. Even we play it safe and suggest that it will take a good 20 years or more to measure the degree to which novel forms of therapy extend healthy life in human patients, that still leaves a good long time for the research and development of rejuvenation therapies aimed at the repair of forms of molecular damage that cause aging.
Still, one can't argue against the diminishing returns produced by the old way of doing things when it comes to treatment and prevention of age-related disease. That encompasses public health measures aimed at reducing smoking (and now obesity, the largest problem of our era, as smoking was the largest problem of a past one), improved wealth, and the introduction of therapies that can modestly slow or reduce some of the consequences of aging without actually addressing its causes. Medicine that reduces blood pressure or lowers LDL-cholesterol, for example. Both are influential in the populations that use it, when considered from an epidemiological viewpoint where a 10-20% risk reduction is sizable across a population. But for an individual, a 10-20% risk reduction isn't all that great. It certainly isn't rejuvenation. But that is what the old approach to age-related disease gave us, marginal therapies, marginal outcomes.
The reason that betting against radical life extension seems foolish is that there are now earnest efforts underway to treat aging as a medical condition, a whole new approach to the problem of age-related disease. None of this has yet to reach the clinic in any widespread way, so who knows how effective the initial therapies will turn out to be. On balance, and over the course of decades, one would have to think that a biotech industry actively trying to slow and reverse aging by addressing its causes will make significantly greater progress towards longer healthy lives than a medical industry that was only trying to treat the symptoms of aging.
Implausibility of radical life extension in humans in the twenty-first century
More than three decades have passed since predictions were made about the upper limits to human longevity. Evidence presented here based on observed mortality trends in the worldʼs eight longest-lived populations and in Hong Kong and the United States, and metrics of life table entropy, indicate that it has become progressively more difficult to increase life expectancy. At ages 65 and older, the observed average rate of improvement in old-age mortality in the longest-lived populations evaluated here was 30.2% from 1990 to 2019. The impact of this level of mortality improvement, if experienced again over the next three decades, would yield only a 2.5-year increase in life expectancy at birth. This is a fraction of the 3-year per decade (for example, 8.7-year increase from 1990 to 2019) gain in life expectancy predicted by those claiming that radical life extension was forthcoming or already here. That is, old-age mortality has not been declining since 1990 at a pace that is even close to the rate of improvement required to achieve radical life extension in this century.
Where uncertainty remains is how much more survival time can be manufactured with the disease model that now prevails (shown here to have a declining influence on life expectancy) and the far greater uncertainty associated with future improvements in survival that may result from the deployment of gerotherapeutics or other advances in medicine that cannot be conceived of today. Because radical lifespan extension brought forth by yet-to-be-developed medical advances cannot be empirically evaluated over short timeframes, a limitation here (and within the field of aging in general) is that it is difficult to justify any numerical estimate of their future influence on life expectancy.
Forecasts about radical life extension in humans thought to be occurring now or projected to do so in the near term have already influenced the operations and financial structure of multiple industries. Results presented here indicate that there is no evidence to support suggestions that most newborns today will live to age 100 because this would first require accelerated reductions in death rates at older ages (the exact opposite of the deceleration that has occurred in the last three decades). Furthermore, even if the 30.2% improvements in mortality in the 65-and-older population observed to have occurred in high-income nations from 1990 to 2019 occurred again, only a small fractional increase in survival to age 100 would ensue.
The evidence presented here indicates that the era of rapid increases in human life expectancy due to the first longevity revolution has ended. Given rapid advances now occurring in geroscience, there is reason to be optimistic that a second longevity revolution is approaching in the form of modern efforts to slow biological aging, offering humanity a second chance at altering the course of human survival. However, until it becomes possible to modulate the biological rate of aging and fundamentally alter the primary factors that drive human health and longevity, radical life extension in already long-lived national populations remains implausible in this century.
Arguing for Cellular Senescence to Emerge from Distinct Underlying Stress Response Modules
https://www.fightaging.org/archives/2024/10/arguing-for-cellular-senescence-to-emerge-from-distinct-underlying-stress-response-modules/
The categorization of cell states into neat taxonomy is an attempt to conceptually simplify a much more complex, analog underlying reality. Any two cells in a given category may be different in ways that turn out to be meaningful in some contexts. So it should be taken as read that the senescent cells that grow in number with age and contribute to age-related disease differ from one another in many ways, and that what we call senescence is at present an oversimplified big tent. It may well turn out require separation into smaller categories to aid continued research and development into ways to reduce the impact of cellular senescence on later life health.
Better understanding the many differences that can exist between any two given senescent cells is of great interest to researchers who are attempting to produce novel senolytic therapies that can selectively destroy these cells. The existing better explored target mechanisms of first generation senolytic drugs produce variable efficacy in clearance of senescent cells depending on tissue type, duration of senescence, reasons for the onset of senescence, and no doubt many other aspects of senescent biochemistry. The best senolytics to date clear only a fraction of senescent cells, that fraction varying by tissue. In today's open access paper, researchers present a view of cellular senescence as an emergent phenomenon driven by a range of distinct stress response packages, a step on the road to better understanding how to produce better senolytic therapies.
Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity
Cellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity (β-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells.
Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples. Genes regulating stress responses - including transcription factors and genes controlling chromatin accessibility - are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner.
We propose that 'senescence' cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, transcription factors, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.
A Comparison of Calorie Restriction and Intermittent Fasting in Genetically Diverse Mice
https://www.fightaging.org/archives/2024/10/a-comparison-of-calorie-restriction-and-intermittent-fasting-in-genetically-diverse-mice/
Both calorie restriction and intermittent fasting slow aging and extend life in short-lived mammals. In the short term, many measures of health are improved. In long-lived mammals such as our own species, the short term effects are very similar, but effects on life span are much smaller. The reasons why this is the case remain to be determined. Cellular biochemistry is enormously complex and calorie restriction and fasting produce sweeping changes in near every aspect of the operation of metabolism. Researchers can point to improvements in autophagy as the likely primary mechanism for benefits, but do not have an understanding as to why improved autophagy affects life span so differently in short-lived versus long-lived mammals.
Studies conducted separately to assess the effects of calorie restriction and intermittent fasting in rodents have generally indicated that calorie restriction has a larger effect on aging and longevity. Today's open access paper reports on a direct comparison between the two strategies in the same study, and comes to much the same conclusion. One novel aspect of the research is the use of genetically diverse mice known as diversity outbred mice, a model more representative of the differences in a natural population of mammals than is the case for the usual lineages with carefully cultivated similar genetics between individuals. This led to some interesting insights into differential effects of low calorie intake between mice with different characteristics.
Dietary restriction impacts health and lifespan of genetically diverse mice
Caloric restriction extends healthy lifespan in multiple species. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice.
We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling, an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life.
Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.
Implanting Senescent Cells into the Skin of Mice Accelerates Multiple Age-Related Declines
https://www.fightaging.org/archives/2024/10/implanting-senescent-cells-into-the-skin-of-mice-accelerates-multiple-age-related-declines/
Cells become senescent at some pace throughout the body and throughout life, largely by reaching the Hayflick limit on replication, but also under other circumstances, such as when a cell sustains potentially cancerous mutational damage. A senescent cell ceases replication and actively secretes pro-inflammatory signals that (a) encourage senescence in bystander cells and (b) attract the attention of the immune system to destroy the senescent cell. This is all find so long as the immune system can destroy senescent cells rapidly enough to prevent their accumulation, but this stops being the case in later life as the immune system declines in effectiveness. Senescent cells accumulate and become disruptive to tissue structure and function.
Researchers have in the past shown that introducing senescent cells into joint tissue in mice is enough to induce or accelerate osteoarthritis. In today's open access paper, researchers report on the introduction of senescent cells into the skin of 3 month old mice, followed by assessment of a range of measures of health 5 months later. Mouse age doesn't linearly relate to human age, but this is roughly equivalent to the range of early 20s to early 40s in humans. One would not expect to see dramatic signs of aging in 8 month old mice, but there are measurable differences, declines in function. This study demonstrates that the presence of a greater burden of senescent cells makes those declines worse.
Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline
Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters.
Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.
A limitation of our study is that the amount and composition of transplanted senescent cells does not accurately reflect senescent cell accumulation during physiological aging. Future research should include other models of senescence induction in the skin, including exposure to physiological levels of UV irradiation. Furthermore, to determine whether paracrine senescence is the causal factor driving the observed aging phenotypes, experiments involving the clearance of senescent cells using senolytic drugs or genetic models that enable the removal of p16 or p21 positive cells should be conducted. In addition, further research is needed to pinpoint which factors released by senescent cells in the skin drive the systemic effects observed in host tissues. Such mechanistic studies could open new avenues for therapeutic intervention.
Yet Another Study of Age-Related Changes Taking Place in the Gut Microbiome
https://www.fightaging.org/archives/2024/10/yet-another-study-of-age-related-changes-taking-place-in-the-gut-microbiome/
The 16S rRNA gene is a component of the ribosome in bacteria. It conveniently contains (a) highly conserved sections, allowing this gene sequence to be reliably found in DNA samples from any bacterial species, but also (b) regions that vary widely by species, allowing for the identification of the bacterial species of origin. Thus the 16S rRNA region of bacterial genomes can cost-effectively sequenced in bulk from any sample, and the data analyzed to produce an assessment of which bacterial species are present, and in what relative proportions. In the case of the gut microbiome, fecal samples lead to a map of the bacterial populations of the intestine.
The composition of the gut microbiome is presently thought to be influential on long term health. The relative proportions of bacterial species making up the gut microbiome change with age, for reasons that include diet and immune system dysfunction, but which are far from fully explored in detail. Nonetheless, in a world in which it costs little to gather this data, greater understanding will come in time. In recent years, the research community has demonstrated correlations between gut microbiome composition and chronological age, as well as the presence of specific age-related conditions. It seems likely based on animal studies that ways to produce lasting, calibrated restoration of a youthful balance of microbial populations can be produced from the starting point of fecal microbiota transplantation, and that this class of therapy will provide to be beneficial for all older people.
Identification of age-associated microbial changes via long-read 16S sequencing
In this study, we investigated the association between age and gut microbial composition in individuals residing in Singapore. To the best of our knowledge, this is the first full-length 16S rRNA gene assessment of the gut microbiota in a multi-ethnic country. Previous studies evaluating the effect of age on the gut microbiome primarily used a short-read 16S rRNA gene sequencing approach. The limited resolution of short-read sequencing often fails to detect bacterial changes at the species/strain level, which can affect data interpretation. In our work, we utilized the long-read sequencing approach to explore age-related gut microbiome alterations for the first time. In addition to replicating previous findings, our study unveiled several novel differentially abundant taxa and predicted functional pathways associated with age.
Despite the insignificant differences in alpha diversity and beta diversity, several differentially abundant bacterial taxa were detected among the age groups. For instance, a notable decrease in Bacteroides uniformis was observed in the gut microbiome of middle-aged individuals, while Bacteroides plebeius was significantly elevated in the old group. These findings align with multiple earlier studies, which reported contrasting findings on the abundances of Bacteroides in the gut microbiome of individuals from different age groups. Some studies documented increased levels in younger adults, while others reported higher abundances in the elderly group. Interestingly, recent investigations have also linked the differential abundance of Bacteroides to the overall health status of the study group. Collectively, these findings underscore the importance of employing sequencing techniques that provide precise taxonomic assignments down to the species/strain level, thereby facilitating a more comprehensive delineation of the gut microbiome and permitting a more accurate understanding of the microbial ecology associated with specific conditions.
In the pairwise comparison between middle-aged and old groups, we found that elderly individuals exhibited a significantly higher abundance of Klebsiella pneumoniae (as well as the Klebsiella genus) in their gut microbiome. The elevated level of K. pneumoniae in older individuals is believed to be associated with factors such as increased use of medication or inflammation linked to interleukin-6, both of which are common in older individuals. This bacterium, which is known to be a pathogen, may contribute to health issues frequently observed in this age group.
Besides replicating previous research findings, our study revealed several novel differentially abundant bacterial species that have not been previously reported. These include increased abundances of Eggerthella lenta in middle-aged participants and reduced levels of Catenibacterium mitsuokai in elderly individuals. E. lenta, a bacterium belonging to the Coriobacteriaceae family, is known as an opportunistic pathogen implicated in various conditions and infections. C. mitsuokai, on the other hand, is generally considered part of the normal human gut microbiome. Previous studies have linked C. mitsuokai with dyslipidemia and insulin resistance, and a higher abundance of the Catenibacterium genus has been associated with a potentially lower risk of frailty. Altogether, these findings suggest potential health implications related to changes in the levels of C. mitsuokai in the gut microbiome. The observed reduction of C. mitsuokai in elderly individuals of our cohort could either reflect age-related alterations in gut microbiome composition or represent a compensatory response to the health changes commonly seen in old individuals.
Exploring Causal Relationships Between Epigenetic Age and Neurodegenerative Disease
https://www.fightaging.org/archives/2024/10/exploring-causal-relationships-between-epigenetic-age-and-neurodegenerative-disease/
Researchers can use the strategy of Mendelian randomization to attempt to explore causation in human epidemiological data, provided that data includes information on gene variants associated with the outcomes of interest. Here, this approach is used to gain some insight into the direction of causation in the relationship between epigenetic age acceleration, an epigenetic age greater than chronological age, and the incidence of neurodegenerative conditions such as Alzheimer's disease.
The causative mechanisms underlying the genetic relationships of neurodegenerative diseases with epigenetic aging and human longevity remain obscure. We aimed to detect causal associations and shared genetic etiology of neurodegenerative diseases with epigenetic aging and human longevity. We obtained large-scale genome-wide association study summary statistics data for four measures of epigenetic age, GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge, (N = 34,710), multivariate longevity (healthspan, lifespan, and exceptional longevity) (N = 1,349,462), and for multiple neurodegenerative diseases (N = 6,618 to 482,730), including Lewy body dementia, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.
Main analyses were conducted using multiplicative random effects inverse-variance weighted Mendelian randomization (MR), and conditional/conjunctional false discovery rate (cond/conjFDR) approach. Shared genomic loci were functionally characterized to gain biological understanding. Evidence showed that AD patients had 0.309 year less in exceptional longevity (inverse-variance-weighted, IVW beta = -0.309). We also observed suggestively significant causal evidence between AD and GrimAge age acceleration (IVW beta = -0.10). Following the discovery of polygenic overlap, we identified rs78143120 as shared genomic locus between AD and GrimAge age acceleration, and rs12691088 between AD and exceptional longevity. Among these loci, rs78143120 was novel for AD.
In conclusion, we observed that only AD had causal effects on epigenetic aging and human longevity, while other neurodegenerative diseases did not. The genetic overlap between them, with mixed effect directions, suggested complex shared genetic etiology and molecular mechanisms.
Immune Cells that Prevent Metastatic Cancer Cells from Proliferating After Migration
https://www.fightaging.org/archives/2024/10/immune-cells-that-prevent-metastatic-cancer-cells-from-proliferating-after-migration/
If there were a reliable way to prevent metastasis, the spread of cancerous cells throughout the body and generation of secondary tumors, few types of cancer would be life-threatening in the context of today's medical capabilities. Thus there is a lot to be said for the various lines of research aimed at finding ways to sabotage metastasis. Here researchers attempt to answer the question of why migrated metastatic cells sometimes fail to establish a secondary tumor, and point to a population of immune cells that may prove to be a useful target for anti-metatasis immunotherapy.
Cells that migrate from primary tumors and seed metastatic tumors are called disseminated cancer cells (DCCs). Some DCCs behave aggressively, immediately starting tumors in new tissue, while others remain in a state of suspended animation referred to as dormancy. "It's long been a mystery how some DCCs can remain in tissues for decades and never cause metastases, and we believe we've found the explanation." Breast cancer and many other types of cancer metastasize to the lungs. In research involving three mouse models of metastatic breast cancer, researchers determined that when breast cancer DCCs spread to the lung's alveoli, they are kept in a dormant state by immune cells known as alveolar macrophages.
Confirming the importance of alveolar macrophages in keeping DCCs dormant, researchers found that depleting them in the mice significantly increased the number of activated DCCs and subsequent metastases in their lungs compared to mice with normal levels of the immune cells. As DCCs become more aggressive, the researchers found, they become resistant to the pro-dormancy signals produced by alveolar macrophages. Ultimately, this evasion mechanism enables some DCCs to "wake up" from dormancy and reactivate to form metastases. Understanding how immune cells keep DCCs in check could lead to new anti-metastatic cell therapies among other strategies. For example, it may be possible to strengthen macrophage signaling so that DCCs never awaken from dormancy or find ways to prevent older DCCs from becoming resistant to dormancy signaling.
Demonstrating Glymphatic Drainage of Cerebrospinal Fluid in Humans
https://www.fightaging.org/archives/2024/10/demonstrating-glymphatic-drainage-of-cerebrospinal-fluid-in-humans/
Channels by which cerebrospinal fluid leaves the brain are important to long term health, as they allow removal of metabolic waste such as the protein aggregates that characterize neurodegenerative conditions. It is thought that atrophy of these channels, including (a) passage through the cribriform plate and (b) the comparatively recently discovered glymphatic system, contributes to the aging of the brain by allowing molecular waste to build up to levels that change cell behavior for the worse. Here researchers repeat in human patients the demonstrations of glymphatic drainage of cerebrospinal fluid that have been carried out in laboratory animals. Leucadia Therapeutics is developing an implant to restore passage through the cribriform plate, but it remains to be seen as to how the more complex dysfunction of the glymphatic system will be best addressed.
The glymphatic pathway was described as a network of perivascular spaces (PVS) that facilitates the organized movement of cerebrospinal fluid (CSF) between the subarachnoid space and brain parenchyma. CSF mixes with interstitial fluid, promoting clearance of soluble by-products from the central nervous system. This is suspected to be impaired in sleep dysfunction, traumatic brain injury, and Alzheimer's disease.
Pioneering glymphatic studies in rodents showed CSF tracer flow through the subarachnoid space and into brain parenchyma along periarterial spaces. Human intrathecal contrast-enhanced MRI similarly demonstrated parenchymal contrast enhancement in a centripetal pattern from the subarachnoid space, providing early evidence for human glymphatic function. The PVS is postulated to be involved in this process, yet perivascular CSF tracer transport has not been observed in humans. This is a proof-of-principle study in which, by using intrathecal gadolinium contrast-enhanced MRI, we show that contrast-enhanced CSF moves through the PVS into the parenchyma, supporting the existence of a glymphatic pathway in humans.
A Metabolomic Profile of Aging Derived from a Large Data Set
https://www.fightaging.org/archives/2024/10/a-metabolomic-profile-of-aging-derived-from-a-large-data-set/
Analysis of large omics data sets in the context of aging and mortality proceeds apace in the research community. On the one hand there is the production of aging clocks, algorithmic combinations of omics data generated via machine learning, in the attempt to produce a useful measure of biological age. On the other hand there are related analyses such as the one noted here, in which researchers attempt to correlate specific individual biomarkers obtained from a blood sample to age and mortality. Many, many metabolites circulate in the body, and it is certainly possible that some of these are better biomarkers for specific uses than the present consensus choices.
The plasma metabolome carries dynamic biological signals that reflect personal health status. Previous studies have demonstrated the potential of metabolomic biomarkers for disease and mortality risk prediction. With the availability of low-cost, standardized, high-throughput nuclear magnetic resonance (NMR) metabolomic profiling and the promotion of blood tests during medical checkups, the identification and quantification of aging-related metabolomic biomarkers hold potential for personalized health monitoring and anti-aging interventions.
Here, we present the largest aging-related metabolomic profile to date based on 325 NMR biomarkers from 250,341 individuals from the UK Biobank. A subset of 54 aging-related representative metabolomic biomarkers were identified based on their ability to predict all-cause mortality. These aging-related biomarkers are involved in diverse biological functions and metabolic pathways, which might serve as potential anti-aging intervention targets and facilitate further exploration of the mechanism of aging-related diseases. High-resolution analysis of the refined composition and structure of multiple lipoprotein-related biomarkers, enabled by NMR profiling, contributes greatly to unraveling the roles of lipid metabolism in the process of aging.
Reviewing What is Known of the Role of the Gut Microbiome in Aging
https://www.fightaging.org/archives/2024/10/reviewing-what-is-known-of-the-role-of-the-gut-microbiome-in-aging/
A growing body of evidence suggests that composition of the gut microbiome - and changes in that composition - may be as influential on long-term health, aging, and age-related disease as well explored lifestyle factors such as exercise. Given the ability to cheaply and accurately determine the identity and size of microbial populations making up the gut microbiome via 16s rRNA sequencing, researchers are finding that many specific aspects of the microbiome both change with age and correlate with specific age-related diseases. The next step is to build robust approaches to producing permanent change in the gut microbiome, such as that achieved via fecal microbiota transplantation from a young donor to an old recipient, but with greater control over exactly what is delivered and the intended outcome.
With the introduction of novel molecular biological techniques and advances in next-generation sequencing technologies, we finally have a snapshot of the gut microbiome and its taxonomical and functional constituents. Various studies have been conducted on healthy elderly individuals to characterize their gut microbiome composition and identify alterations that help delay the onset of age-associated disorders. Although aging is a complex biological process that has yet to be fully understood, we have an increasing volume of evidence supporting the existence of a dialogue between the gut microbiome of a host and its aging process. Aging brings about changes in the gut microbiome, disrupting its balance and functionality, which can accelerate senescence through inflammatory processes and reduced production of beneficial metabolites.
Advancements in the different "omics" fields have provided us with a clear understanding of various host-microbe interactions and their influences on aging. Enrichment of certain taxa, such as Bifidobacterium, Christensenellaceae, and Akkermansia, has been shown to promote longevity and improve quality of life during senescence. To improve the gut microbiome and encourage healthy aging, techniques such as fecal microbiome transplantation (FMT) and oral probiotic treatment have been used. Administration of prebiotics and probiotics may mitigate age-related alterations linked to sarcopenia and longevity.
Since age-related disorders are known to increase intestinal permeability, regaining intestinal permeability by FMT may be a regenerative and successful medicinal technique in producing stem cells for the elderly. Nevertheless, more research is needed to determine whether FMT to old recipients from young donors restores the ability of stem cells to self-renew, regenerate, and differentiate, thereby improving lifespan. To pave the way for discovering therapeutic medications for extending lifespan and treating disorders linked to aging, more research into the interactions between intestinal stem cells and the microbiome is necessary.
Investigating the Age-Related Decline of Choroid Plexus Function
https://www.fightaging.org/archives/2024/10/investigating-the-age-related-decline-of-choroid-plexus-function/
The choroid plexus is a structure responsible for producing and filtering cerebrospinal fluid, but likely has other important roles as well. The production of cerebrospinal fluid declines with age for reasons that are not all that well explored. A reduced flow of cerebrospinal fluid through the brain likely contributes to brain aging via an increased presence of the metabolic waste that is normally drained from the brain via cerebrospinal fluid flow. Hence the occasional paper such as this one, in which researchers attempt to make some inroads into mapping the age-related biochemical changes that take place in cells of the choroid plexus, one small step along the way to the construction of a bigger picture view of how aging affects the choroid plexus.
The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1).
CSF is composed of 99% water, and the remaining 1% is accounted for by proteins, ions, neurotransmitters, and glucose. A high water permeability of the blood-cerebrospinal fluid barrier (BCSFB), a physicochemical barrier established by choroid plexus (CP) epithelial cells, is essential for the optimal production of the CSF, and this is met by the abundant expression of water channels AQP4 and AQP1. CSF enters from the perivascular spaces surrounding arteries into the brain parenchyma through the AQP4 water channels in the astrocytic end-feet. AQP1 is a cGMP-gated cation channel that serves as a water channel and a gated ion channel in the choroid plexus, contributing to the regulation of CSF production.
Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJPs were also reduced in aged mice.
Our study highlights transcriptional level changes in the CP during aging. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.
Senescent Microglia are Likely Important in Age-Related Neurodegeneration
https://www.fightaging.org/archives/2024/10/senescent-microglia-are-likely-important-in-age-related-neurodegeneration/
Evidence from animal studies strongly suggests an important role for cellular senescence in supporting cell populations in the brain in driving the onset and progression of age-related neurodegenerative conditions. Senescent cells accumulate with age in tissues throughout the body, the result of growing cell stress resulting from the molecular damage and disarray of aging on the one hand, but on the other hand also the problem of inefficient clearance, resulting from the growing inability of the immune system to destroy senescent cells in a timely fashion. Senescent cells energetically secrete a pro-inflammatory mix of signals, disruptive to tissue structure and function when sustained over the long term.
The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression.
Recent research has linked disease-associated microglia to their transition into a senescent state - characterized by irreversible cell cycle arrest - in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets.
This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.
More Selective Disruption of Growth Hormone Metabolism in Mice Still Extends Life
https://www.fightaging.org/archives/2024/10/more-selective-disruption-of-growth-hormone-metabolism-in-mice-still-extends-life/
The most well-studied mouse models of extended life span resulting from disrupted growth hormone signaling involve genetic changes that likely do more than just affect growth hormone metabolism. The usual challenges of cellular biochemistry apply, in that most proteins have more than one function. Here, researchers show that a selective knockout of only growth hormone still extends life, but not to the same extent as is observed in the better known models. Looking at the broader context of the influence of growth hormone metabolism on aging, it is worth recalling that the analogous human loss of function mutants, the condition known as Laron syndrome, do not appear to live notably longer than the rest of the population. As is the case for calorie restriction, effects in short lived species are larger than those in long-lived species such as our own.
The somatotrophic axis, comprised of growth hormone (GH) and GH-releasing hormone (GHRH) secreted from the pituitary or hypothalamus, respectively, is a powerful determinant of laboratory mouse longevity evidenced by the dramatic lifespan extensions that result from genetic interruption at any level of this axis in mice. This body of work suggests that the action of GH is a critical regulator of mammalian lifespan. A crucial limitation of these studies, however, is that mice typically treated as "GH-deficient" display defects in several other genes and hormones which leaves the direct contribution of GH unexplored.
Ames dwarf and Snell dwarf mice, deficient for GH as well as prolactin and thyroid-stimulating hormone, were among the first mice with defective somatotrophic signaling found to be long-lived. Mutant mice lacking a functional GHRH-receptor or functional GHRH also cannot be considered true models of "isolated GH deficiency" as the extrapituitary effects of GHRH, which have gained appreciation as important physiological regulators, could contribute to the lifespan extension reported in these mice. Additionally, mice with a targeted disruption of the GH-receptor (GHR) gene display dramatically elevated levels of GH.
To address this critical gap in knowledge, we carried out the first assessment (to our knowledge) of lifespan in mice with a targeted GH gene knockout in conjunction with metabolic assessment during adulthood. GH knockout (KO) mice maintained under specific pathogen-free conditions with ad-libitum access to standard rodent diet and water displayed a 21% extension in median lifespan over wild type littermates. It is noteworthy that while the differences in lifespan we observed between KO and wild type mice were significant, they are lesser in magnitude than the 40+% extensions reported in other models of somatotrophic disruption. This suggests that while GH deficiency clearly contributes to lifespan extension, an additive effect of additional gene/hormone deficiencies on lifespan may also exist.
Upregulation of aal1 Long Non-Coding RNA Extends Life in Flies
https://www.fightaging.org/archives/2024/10/upregulation-of-aal1-long-non-coding-rna-extends-life-in-flies/
Researchers here report on the discovery of a long non-coding RNA that in flies reduces the pace of creation of ribosomes, and thus the pace of protein synthesis in ribosomes, by inhibiting production of a specific ribosomal protein. The result is extended lifespan. This is intriguing, as improving ribosomal function has been shown to extend life in short-lived species, and this does not have the look of an improvement. But equally, there are signs that long-lived individuals may exhibit reduced creation of ribosomes. Protein synthesis in ribosomes is also reduced in a number of life extending interventions, such as calorie restriction and its mimetics. As for all matters of cellular biochemistry in the context of aging, the influence of ribsosomal activity is complex and the fine details matter.
Genomes produce widespread long non-coding RNAs (lncRNAs) of largely unknown functions. We characterize aal1 (ageing-associated lncRNA), which is induced in quiescent fission yeast cells. Deletion of aal1 shortens the chronological lifespan of non-dividing cells, while ectopic overexpression prolongs their lifespan, indicating that aal1 acts in trans. Overexpression of aal1 represses ribosomal-protein gene expression and inhibits cell growth, and aal1 genetically interacts with coding genes functioning in protein translation. The aal1 lncRNA localizes to the cytoplasm and associates with ribosomes. Notably, aal1 overexpression decreases the cellular ribosome content and inhibits protein translation.
The aal1 lncRNA binds to the rpl1901 mRNA, encoding a ribosomal protein. The rpl1901 levels are reduced ~2-fold by aal1, which is sufficient to extend lifespan. Remarkably, the expression of the aal1 lncRNA in Drosophila boosts fly lifespan. We propose that aal1 reduces the ribosome content by decreasing Rpl1901 levels, thus attenuating the translational capacity and promoting longevity. Although aal1 is not conserved, its effect in flies suggests that animals feature related mechanisms that modulate ageing, based on the conserved translational machinery.
Characterizing Senescent Cell Burden in Skin
https://www.fightaging.org/archives/2024/10/characterizing-senescent-cell-burden-in-skin/
Researchers here work towards developing a better characterization of the age-related burden of senescent cells in skin tissue. As for all tissues in the body, the number of senescent cells in skin grows with age. This is the result of an imbalance between pace of creation and pace of clearance by the immune system; with age, cell stress increases while the capabilities of the immune system decline. Lingering senescent cells constantly secrete pro-inflammatory signals, and this contributes to body-wide inflammation. Skin is a large organ, and provides a meaningful fraction of this contribution of senescent cells to the whole body chronic inflammation of aging.
Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and cell-extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging.
A skin-specific cellular senescence gene set, termed SenSkin, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.
View the full article at FightAging
