Fight Aging!

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.

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 reflecting 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.

Link: https://doi.org/10.1038/s41467-024-52310-9

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.

Link: https://doi.org/10.1073/pnas.2407246121

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 the suggestion 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.

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.

Link: https://www.eurekalert.org/news-releases/1060251

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.

Link: https://doi.org/10.1111/acel.14271

Past studies have demonstrated that the economic cost of aging is enormous. It is not just a matter of the high medical cost of coping with a failing body and a panoply of conditions that cannot presently be cured or even much reversed. The lifetime cost of treating only cardiovascular disease is something like $750,000, for example. There is also the constant destruction of knowledge, capability, and ability to work. There is the opportunity cost of actions that cannot be taken. If everyone in the US gained a year of additional life, if aging was slowed by one year, $38 trillion in economic gains per year would be realized. These are staggering numbers.

In today's open access papers, the authors take a different approach to looking at the value of treating aging as a medical condition. What if every region of the world could adopt the age-related mortality of the best performing region? For each major cause of aging the authors take mortality rates in the best performing region as a benchmark, and consider mortality above this level to be avoidable. Which may or may not be entirely the case, but it is a decent place to start if running the numbers on what an incremental, near future advance in the treatment of aging might look like. As one might expect, the numbers are still very large.

Why do the differences between regions exist? Largely lifestyle choices, and then a layer of socioeconomic status and access to medical technologies on top of that. When it comes to cardiovascular disease risk, the average American is not outperforming the average Bolivian hunter-gatherer, despite the vast disparity in wealth. So strictly speaking, this isn't a discussion about medical technology. Nonetheless, the numbers are interesting in a world in which we may expect the near future introduction of treatments for aging that could have similar effect sizes to exercise, calorie restriction, weight loss, and other lifestyle considerations.

The economic value of reducing avoidable mortality

Living longer and healthier boosts individual and family welfare. As part of the World Bank's Healthy Longevity Initiative, we quantified the economic value of achieving the highest possible life span. We estimated the economic value of reducing avoidable mortality, defined as the difference between observed (or projected) mortality and lowest achieved (or projected) mortality, by world regions, sex, and age, between 2000 and 2021, with projection to 2050.

In 2019, 69% of mortality, or 40 million deaths, was avoidable. The economic value of avoidable mortality globally was 23% of annual income, meaning that, globally, populations would be willing to give up about one-fifth of their current income in exchange for a year living at the lowest achieved mortality rate. This value ranges from 19% in China to 34% in sub-Saharan Africa. Under the rapid-progress scenario, in which countries experience fast but plausible mortality reductions from 2019 to 2050, we would expect globally the gap between projected and frontier life expectancy to be halved by 2050, and the economic value after achieving this scenario is equivalent to 14% of annual income. Our work provides supportive evidence on the high economic value placed on improving health.

The economic value of reducing mortality due to noncommunicable diseases and injuries

With population aging, national health systems face difficult trade-offs in allocating resources. The World Bank launched the Healthy Longevity Initiative to generate evidence for investing in policies that can improve healthy longevity and human capital. As part of this initiative, we quantified the economic value of reducing avoidable mortality from major noncommunicable diseases and injuries. We estimated avoidable mortality - the difference between lowest-achieved mortality frontiers and projected mortality trajectories - for each cause of death, for 2000, 2019 and 2050, and for geographic regions, with high-income countries, India and China considered separately; we applied economic values to these estimates.

The economic value of reducing cardiovascular disease avoidable mortality would be large for both sexes in all regions, reaching 2-8% of annual income in 2019. For cancers, it would be 5-6% of annual income in high-income countries and China, and for injuries, it would be around 5% in sub-Saharan Africa and Latin America and the Caribbean. Despite the large uncertainty surrounding our estimates, we offer economic values for reducing avoidable mortality by cause and metrics comparable to annual incomes, which enable multisectoral priority setting and are relevant for high-level policy discussions around budget and resource allocations.

The interior of blood vessels is lined by the endothelium. With aging, cells of the endothelium exhibit stress, inflammation, and altered behavior, contributing to the development of atherosclerosis and negatively affecting performance of the vasculature. Here, researchers discuss the degree to which this aspect of degenerative aging is caused by the presence of senescent cells. Cells become senescent constantly throughout life, but in youth are cleared efficiently by the immune system. This clearance falters later in life, allowing senescent cells to grow in number to the point of becoming disruptive to tissue structure and function. Senolytic therapies to selectively clear senescent cells have proven to be beneficial in animal studies and are presently in human trials for a number of age-related conditions.

Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence.

We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-β-Gal was quantified. We found a negative correlation in passaged cell cultures between a reduction in NO production with increased ES and the formation of reactive oxygen species and reactive nitrogen species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN).

Thus NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response.

Link: https://doi.org/10.3390/ijms25189890

The metabolic responses to exercise and calorie restriction are so sweeping that there are many, many possible avenues by which drugs can mimic some of the effects. Researchers here try to get closer to the roots of these beneficial responses by using a molecule that will trigger the same reactions as two circulating signal molecules known to be important in regulating the response to exercise and fasting. This seems a reasonable strategy to try to capture a larger fraction of the benefits of exercise and fasting, but of course much more work is needed in order to see how this approach matches up to the sizable number of existing exercise mimetic and calorie restriction mimetic interventions.

Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest.

In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).

Link: https://doi.org/10.1021/acs.jafc.4c04849

Stem cell populations provide a supply of daughter cells needed for tissue function, but their activity - and this supply of new cells - declines with age. Stem cell populations can shrink in size, but aged stem cells also spend more time in quiescence rather than the production of daughter cells. This happens due to some combination of (a) age-related damage to stem cells and (b) age-related damage to the stem cell niche, the supporting cells that provide an environment in which the stem cells reside. For many stem cell types, researchers have demonstrated that old stem cells become more active when placed in a young environment, which suggests that there will be ways to improve stem cell function in older individuals.

The traditional approach to finding approaches to stem cell functional restoration, or indeed any other goal in medicine, is to (a) identify regulatory genes controlling the process of interest, here the maladaptive reduction in stem cell activity in response to an aged tissue environment, then (b) find small molecules that alter expression or protein interactions to either upregulate or downregulate the activity of a target regulatory gene. Today's open access paper is an example of the first step, in which researchers search for genes regulating the activity of neural stem cells. The generation of new neurons by neural stem cell populations and their subsequent integration into neural circuits is vital to memory and learning, but also critical to what little capacity the brain has to maintain itself and recover from injury. As for all stem cell populations, the activity of neural stem cells is reduced in older people. Forcing these cells back into action may produce a beneficial improvement in cognitive function.

CRISPR-Cas9 screens reveal regulators of ageing in neural stem cells

Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing. Several genetic interventions have been found to ameliorate old brain function, but systematic functional testing of genes in old NSCs - and more generally in old cells - has not been conducted. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice.

Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR-Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age.

Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing.

Cognitive function declines with advancing age. The brain accumulates damage at the biochemical level, but also in the form of ruptured blood vessels and microbleeds. Supporting cells become inflammatory, myelin sheathing of axons becomes damaged, the delicate balance of complex mechanisms that supports the activities and connections of neurons runs awry. Add a stroke to all of this, and the pace of decline accelerates afterwards. The reasons why this is the case are likely more complex than simply an additional burden of inflammation, and the epidemiological paper here only demonstrates the outcome, not the mechanisms.

Stroke is a leading cause of disability and dementia worldwide, with projections suggesting a continued rise in its prevalence and burden. Recent studies have shown that cognitive impairment is highly prevalent after stroke, with cognitive deficits present in over a third of stroke survivors. However, the precise impact of stroke on the trajectory of cognitive function remains unclear. Previous studies, primarily hospital-based, have been unable to account for prestroke cognitive performance, and several population-based studies examining prestroke and poststroke cognitive function reported conflicting findings, likely due to variations in study design, sample characteristics, and statistical techniques.

This study aimed to address these inconsistencies by mapping the trajectory of cognitive function after stroke relative to the cognitive trajectory without a previous stroke using harmonized data from diverse population cohorts from the Cohort Studies of Memory in an International Consortium (COSMIC). The study included 20,860 participants with a mean (standard deviation, SD) age of 72.9 (8.0) years and follow-up of 7.51 (4.2) years. Incident stroke was associated with a substantial acute decline in global cognition (-0.25 SD), the Mini-Mental State Examination, and all cognitive domains (ranging from -0.17 SD to -0.22 SD), as well as accelerated decline in global cognition (-0.038 SD per year) and all domains except memory (ranging from -0.020 to -0.055 SD per year), relative to a stroke-free cognitive trajectory. There was no significant difference in prestroke slope in stroke survivors compared with the rate of decline in individuals without stroke in all cognitive measures.

Thus in this cohort study using pooled data from 14 cohorts, incident stroke was associated with acute and accelerated long-term cognitive decline in older stroke survivors.

Link: https://doi.org/10.1001/jamanetworkopen.2024.37133

Researchers here find a role for TIMP3 overexpression in the progression of macular degeneration, an age-related deterioration of the retina that causes blindness. Interestingly, TIMP3 was previously shown to contribute to the age-related decline in stem cell function, and its removal appears beneficial in aged mice. The research noted here was conducted in vitro, using stem cells as a rough model of macular degeneration, which may explain why TIMP3 appeared as a relevant mechanism. It pays not to be too excited by research of this nature until positive results are produced in animal models, however.

The study utilized human stem cells to model age-related macular degeneration (AMD), overcoming the limitations of previous research using animal models. By examining genes associated with both AMD and rarer inherited forms of blindness called macular dystrophies, the researchers identified a key protein involved in the early stages of the disease. The retinal pigment epithelium (RPE), a layer of cells at the back of the eye, plays a crucial role in AMD. Over time, deposits of lipids and proteins, known as drusen, accumulate in the RPE. These deposits are often an early indicator of AMD.

The researchers discovered that a protein called tissue inhibitor of metalloproteinases 3 (TIMP3) is overproduced in AMD. TIMP3 inhibits the activity of enzymes called matrix metalloproteinases (MMPs), which are essential for eye health. Impaired MMP activity leads to increase in another enzyme which promotes inflammation and the formation of drusen. By using a small molecule inhibitor to block the activity of the enzyme associated with inflammation, the researchers were able to reduce drusen formation in their model, suggesting that targeting this pathway could be a promising strategy for preventing AMD.

Link: https://www.eurekalert.org/news-releases/1059721

The composition of the gut microbiome is influential on long term health and aging, possibly to a similar degree to lifestyle choices such as degree of physical exercise. Data shows that the relative sizes of microbial populations in the gut change with age in ways that provoke greater inflammation and reduce the production of beneficial metabolites. Conversely, it appears possible to produce lasting change in the gut microbiome, such as via fecal microbiota transplantation or therapies that cause the immune system to ramp up its destruction of problematic microbial species.

These approaches have yet to make their way into human medicine in any sizable way because regulators require a great deal more characterization of the microbiome and its alterations than presently exists. For example, given that microbial contributions to disease are far from fully mapped, and may proceed slowly over time, it is presently impossible to state in certainty that a fecal microbiota transplant will not introduce some novel problem for the recipient.

Nonetheless, there is considerable motivation to find ways to engineer therapeutic changes in the gut microbiome. Today's open access paper is one example of a continued flow of reviews and findings that report on distinct features of the gut microbiome in patients suffering from specific age-related conditions. Find ways to remove those features from the microbiome may turn out to be a viable approach to therapy for much of the panoply of age-related dysfunction and decline.

Association of Gut Microbiome with Muscle Mass, Muscle Strength, and Muscle Performance in Older Adults: A Systematic Review

Sarcopenia, characterized by age-related decline in muscle mass and function, significantly increases the risk of adverse outcomes such as impaired quality of life, falls, hip fractures, frailty, hospitalization, disability, and mortality. Individuals with sarcopenia have a higher likelihood of premature mortality compared to their age-matched counterparts. Sarcopenia also strongly predicts disability, defined as limitations in activities of daily living (ADL) and care home admissions. However, it is plausible that age-associated modifications in the gut microbiota and muscle tissue composition could be driven by shared underlying processes, such as chronic inflammation, dysfunction of the immune system, and changes in hormone levels, which could influence both microbiota alterations and the onset of sarcopenia.

Currently, there is no single effective therapeutic intervention for sarcopenia. The 'gut-muscle axis', which explores how the gut microbiome affects muscle mass, strength, and function in older adults, plays a crucial role in both the prevention and management of sarcopenia. Previous research indicates that diet composition and the gut microbiome change with age and are correlated with muscle mass decline, thereby impacting physical performance. Advanced age leads to gut microbiome dysbiosis, characterized by altered microbial diversity, predominant bacteria, and reduced beneficial bacterial metabolites. These biological processes, particularly those related to inflammation and the immune system, are greatly influenced by the gut microbiome. Studies show differences in gut microbiome composition, measured using RNA sequencing, between older and younger participants, marked by variations in alpha diversity//en.wikipedia.org/wiki/Alpha_diversity">alpha diversity (species diversity within a sample) and beta diversity (species diversity between samples). Animal studies support these findings, suggesting that variations in the gut microbiome and metagenome influence biological processes such as inflammation, nutrient bioavailability, and lipid metabolism, contributing to age-related muscle decline.

This review provides insight into potential novel interventions for sarcopenia prevention and treatment. A systematic search was conducted for studies published between 2002 and 2022 involving participants aged 50+. Studies were included if they assessed sarcopenia using at least one measure of muscle mass (skeletal muscle mass, bioelectrical impedance analysis, MRI), muscle strength, or muscle performance. The microbiome was measured using at least RNA/DNA sequencing or shotgun metagenomic sequencing. Twelve studies were analyzed. Findings revealed that a higher abundance of bacterial species such as Desulfovibrio piger, and Clostridium symbiosum and reduced diversity of butyrate-producing bacteria was associated with sarcopenia severity, as indicated by decreased grip strength, muscle mass, or physical performance. The gut microbiome plays a significant role in age-related muscle loss. Probiotics, prebiotics, and bacterial products could be potential interventions to improve muscle health in older adults.

The most widely used epigenetic clocks are built on DNA methylation data obtained from immune cells in blood samples. The research of recent years has indicated that different types of immune cell exhibit quite different characteristics of epigenetic aging, leading to some ongoing debate as to how best to interpret this data. There are other easily obtained sources of cells that lack this issue, however, such as a buccal swab of the interior of the cheek. Here, researchers discuss the ongoing development of CheekAge, a clock built on DNA methylation data obtained from a large buccal swab data set.

While earlier first-generation epigenetic aging clocks were trained to estimate chronological age as accurately as possible, more recent next-generation clocks incorporate DNA methylation information more pertinent to health, lifestyle, and/or outcomes. Recently, we produced a non-invasive next-generation epigenetic clock trained using DNA methylation data from more than 8,000 diverse adult buccal samples. While this clock correlated with various health, lifestyle, and disease factors, we did not assess its ability to capture mortality. To address this gap, we applied CheekAge to the longitudinal Lothian Birth Cohorts of 1921 and 1936.

To our knowledge, this is the first study to demonstrate that an aging biomarker optimized for buccal tissue can be applied to blood for mortality prediction. Our findings build on previous work from more than a decade ago, which found that buccal methylation data was highly informative for a variety of phenotypes and diseases. The magnitude of the hazard ratio for mortality prediction outcompetes all first-generation clocks tested and compares favorably to the next-generation blood-trained clock DNAm PhenoAge. These data suggest that adult buccal tissue, which is relatively painless and easy to collect in a variety of settings, may represent a rich source of aging biomarkers.

Link: https://doi.org/10.3389/fragi.2024.1460360

More funding is devoted to the exploration of partial reprogramming than any other approach to the treatment of aging as a medical condition, arguably more funding than all of the other approaches combined. Partial reprogramming recaptures processes that take place in early embryonic development, and is a matter of exposing aged cells to the Yamanaka factors for long enough to produce restoration of youthful epigenetic patterns, but not for so long as to produce a transformation of state into induced pluripotent stem cells. The present consensus is that this balance will be challenging to achieve safely in the context of a drug delivered to much of the body, where the right exposure time differs from cell type to cell type, but that isn't stopping researchers and companies from making the attempt.

Recent studies have shown that limited use of Yamanaka factors or chemicals that mimic their effects can partially reverse cellular or organismal aging. This has been observed in both in vitro human and mouse models, as well as in vivo mouse studies, without fully de-differentiating cells into a pluripotent state. These studies encompass various models, including healthy aged and diseased mice, such as progeroid mice, and involve pulsed, short-term, and medium-term reprogramming regimes; these we call "partial reprogramming" as long as no induction of pluripotency is observed.

Comparing in vitro and in vivo mouse studies, and in vitro studies in humans, supported by visualizations of the interconnections among the data, we show consistent patterns in how such reprogramming modulates key biological processes. Generally, it leads to enhanced chromatin accessibility, upregulation of chromatin modifiers, and improved mitochondrial activity. These changes are accompanied by shifts in stress response programs, such as inflammation, autophagy, and cellular senescence, as well as dysregulation of extracellular matrix pathways.

Ultimately, until we achieve a more robust understanding of aging at the molecular level - and identify much more reliable biomarkers of biological age - the extent to which reprogramming can reverse aging will remain unclear. The effects and potential side effects of reprogramming are context-dependent, varying with the specifics of the reprogramming protocol (such as duration) and the characteristics of the target, including species and tissue or cell types involved. Nonetheless, reprogramming holds significant promise in reversing various biomarkers of aging.

Link: https://doi.org/10.20944/preprints202410.0122.v1