Fight Aging!

What can be found in a human blood sample that either correlates with or predicts exceptional healthspan or lifespan? Quite the variety of research efforts touch on this question, from the development of aging clocks to the construction of omics databases for blood and tissue samples taken from centenarians. People age as a result of the same underlying processes of damage and dysfunction, but the pace of aging clearly varies widely. It is generally accepted in the research community that efficient ways to measure the state of biological aging are needed in order to speed the development of therapies to treat aging. Without the ability to rapidly determine the effects of an alleged anti-aging therapy immediately after administration, the only recourse is to wait and see. Thus animal studies are expensive and slow, research can be stuck for years in a dead end that only later is shown to be not so great, and human data is non-existent, as no-one will fund ten year clinical studies for potential drugs.

Today's open access review paper surveys some of the work conducted to date in search of signatures of longevity that can be measured in blood samples and other non-invasive assays. In some cases, signatures can be plausibly connected to processes relevant to longevity, such as suppression of the chronic inflammation of aging. In other cases, no-one really knows why the correlation exists. It also remains a question, on a case by case basis, as to whether ways to adjust the signature will also slow aging to some degree; in most cases, probably not, as the signature is a downstream consequence of underlying processes and causes little further harm in and of itself.

The Biomarkers in Extreme Longevity: Insights Gained from Metabolomics and Proteomics

In this review, we integrate longevity-related biomarkers discovered by metabolomics and proteomics and further categorize them based on different classes. The mechanisms of longevity-related metabolites have been elucidated, especially for specific fatty acids like EPA, DHA, and short-chain fatty acids, which effect lifespan by reducing inflammation and activating the Nrf2 pathway. The mechanisms underlying the health benefits of the changes in certain metabolites are still largely unknown. For example, the mechanism of some isomers of secondary bile acids affects the body's immunity remains to be further studied. Additionally, the metabolic pathways and products of metabolites should also be considered. Some intermediates (such as kynurenic acid) have neuroprotective effects, which were produced from tryptophan. Regarding proteins, APOE, FOXO, and SIRT are essential signaling proteins for cell survival, which can regulate cell proliferation, metabolism, inflammation, and stress responses by influencing multiple signaling pathways, including PI3K/Akt, NF-κB, etc. Moreover, post-translational modifications such as nitrosylation and glycosylation have important effects on the function and communication of proteins. The interaction between various modifications and star proteins creates a complex network that modulates cell survival to extend lifespan. Therefore, integrating candidate longevity-related biomarkers to conduct a "biomarker library of health and longevity" can further grasp the profile of centenarians or extreme longevity in humans and provide a theoretical foundation for anti-aging.

Appropriate analytical methods are crucial for different research objects based on the research question and sample characteristics. In metabolomics, untargeted and targeted metabolomics both have different advantages and disadvantages. It is worth noting that a certain degree of lipid metabolism dysfunction and neural functional damage happens during the aging process. Therefore, targeted metabolomics focusing on specific metabolites such as short-chain fatty acids, bile acids, and neurotransmitters can better reflect the physiological status of the elderly. In proteomics, general proteomics can provide a more comprehensive protein map for the longevity population. With an increase in age, protein homeostasis gradually declines and results in wrong translation modification such as nitrosylation and glycosylation. Consequently, post-translational modifications of proteins are considered crucial indicators affecting the function of proteins. The study of longevity cohorts based on untargeted metabolomics and general proteomics has been extensively reported. We regard that targeted metabolomics and PTM proteomics focusing on specific biomolecules will attract more attention in aging studies to discover more valuable longevity-related biomarkers, whether metabolites or proteins. Moreover, blood and fecal samples are commonly preferred for biomarker discovery due to their relatively easy access. If tissue-specific characteristics are exhibited in the liver or muscle tissues of centenarians, it potentially leads to obvious alterations in circulating blood metabolites. However, there are significant challenges in obtaining tissue samples such as liver and muscle from living individuals. We wish that better technology may have appeared in the future to offer the possibility to analyze the tissue or organ specificity of centenarians.

Researchers here review the evidence for age-related loss of mitochondrial function to contribute to degenerative disc disease. It is certainly a contribution, but as for every aspect of aging it is very challenging to determine how important any given contribution is versus all of the others. So yes, mitochondrial quality control falters with age, and mitochondria become more damaged and dysfunctional as a result. This happens throughout the body. But is it more or less important for disc degeneration specifically than, say, the chronic inflammation of aging? Absent ways to individually fix each aspect of aging, so that results of treatment can be observed and compared directly, it is difficult to mount compelling arguments.

Intervertebral disc degeneration is the most common disease in chronic musculoskeletal diseases and the main cause of low back pain, which seriously endangers social health level and increases people's economic burden. Disc degeneration is characterized by nucleus pulposus (NP) cell apoptosis, extracellular matrix degradation, and disc structure changes. It progresses with age and under the influence of mechanical overload, oxidative stress, and genetics.

Mitochondria are not only the energy factories of cells, but also participate in a variety of cellular functions such as calcium homeostasis, regulation of cell proliferation, and control of apoptosis. The mitochondrial quality control system involves many mechanisms such as mitochondrial gene regulation, mitochondrial protein import, mitophagy, and mitochondrial dynamics. A large number of studies have confirmed that mitochondrial dysfunction is a key factor in the pathological mechanism of aging and intervertebral disc degeneration, and balancing mitochondrial quality control is extremely important for delaying and treating intervertebral disc degeneration.

In this paper, we first demonstrate the molecular mechanism of mitochondrial quality control in detail by describing mitochondrial biogenesis and mitophagy. Then, we describe the ways in which mitochondrial dysfunction leads to disc degeneration, and review in detail the current research on targeting mitochondria for the treatment of disc degeneration, hoping to draw inspiration from the current research to provide innovative perspectives for the treatment of disc degeneration.

Link: https://doi.org/10.1186/s12967-024-05943-9

In mice, senolytic therapies to clear senescent cells seem such a panacea for age-related conditions that it is always interesting to see evidence for an aspect of aging that is not helped by removal of a portion of the burden of lingering senescent cells. Here, researchers show that senolytics do nothing to help aged mice resist influenza infection if they are administered during or shortly before exposure. Based on what is known of the role of cellular senescence in aging, one would expect an aged mouse that has been treated once with senolytics to later be more resilient to stresses of all sorts, but it likely takes some time for the benefits to be realized, longer than was allowed for here.

Aging is a major risk factor for poor outcomes following respiratory infections. In animal models, the most severe outcomes of respiratory infections in older hosts have been associated with an increased burden of senescent cells that accumulate over time with age and create a hyperinflammatory response. Although studies using coronavirus animal models have demonstrated that removal of senescent cells with senolytics, a class of drugs that selectively kills senescent cells, resulted in reduced lung damage and increased survival, little is known about the role that senescent cells play in the outcome of influenza A viral (IAV) infections in aged mice.

Here, we tested if the aged mice survival or weight loss IAV infections could be improved using three different senolytic regimens. We found that neither dasatinib plus quercetin, fisetin, nor ABT-263 improved outcomes. Furthermore, both dasatanib plus quercetin and fisetin treatments further suppressed immune infiltration than aging alone. Additionally, our data show that the short-term senolytic agents do not reduce senescent markers in our aged mouse model. These findings suggest that acute senolytic treatments do not universally reverse aging related immune phenotype against all respiratory viral infections.

Link: https://doi.org/10.1111/acel.14437

Senescent cells are created constantly throughout life, largely as somatic cells reach the Hayflick limit on replication, but also in response to cell damage and stress. In youth, the immune system rapidly removes these cells. With age, immune clearance falters and lingering senescent cells grow in number in tissues throughout the body. These cells secrete a potent mix of pro-inflammatory signals that can be beneficial in the short term, drawing the attention of the immune system to potential problems, but this signaling becomes disruptive to tissue structure and function when sustained over the long term. The greater the number of senescent cells, the worse the consequent chronic inflammation and harmful outcomes. This is a significant contribution to degenerative aging.

While the development of therapies to selectively destroy senescent cells is very much an ongoing concern, with the first few drugs in clinical trials for several years now, finding a convenient measure to assess the burden of cellular senescence has proven to be harder than expected. One can always take a tissue biopsy and count senescent cells via histology, but this is far from convenient. For all that these cells secrete a wide range of well-known inflammatory signals, the amounts in circulation that can be assessed via a blood sample do not correlate well to the burden of senescent cells. There are too many other sources and sinks operating, muddying the waters. Similarly, directly assessing senescence in white blood cells from a blood sample doesn't map well to the global burden of such cells in tissues, as the immune system is subject to stresses that are very different from those associated with cells in tissues.

Still, it seems plausible that there must be some useful measure of the burden of senescence that can be obtained from circulating signal molecules. In today's open access paper, researchers put forward IL-23R as a candidate for that molecule. If validated, this should help to speed the development of more effective senolytic therapies to clear senescent cells from the aged body and brain.

IL-23R is a senescence-linked circulating and tissue biomarker of aging

Characteristic properties of senescent cells include upregulation of cell cycle regulatory proteins, including p16ink4a, the senescence-associated secretory phenotype (SASP), and activation of senescent cell anti-apoptotic pathways (SCAPs). The SASP is cell-type- and context-specific and can confer adverse changes to local tissue environments and systemic organs. Use of the p16-InkAttac transgenic model, which permits systemic clearance of p16-positive cells through a temporally controlled suicide gene, has demonstrated that senescent cell deletion alleviates features of age-related pathology in several organs, including kidney, adipose, skeletal muscle, eye, heart, and brain. A recent comparison of cell-type-specific versus whole-body transgenic targeting of p16-postitive cells demonstrated greater benefits in aged bone composition following systemic clearance, which supports the notion that the adverse influence of senescent cells and the SASP results from both local and distant signaling.

Despite considerable senolytic testing underway in preclinical models and humans, understanding of the comparative effects of senolytic drugs and senescent cell targeting efficiency across tissues is limited. The central goal of this study was to identify age- and senescence-related plasma and tissue biomarkers that are responsive to senotherapeutic intervention. We assessed system-wide profiles of senescence, SASP, and inflammatory biomarkers in aging and their alteration by clinically relevant senolytic compounds versus transgenic p16-InkAttac senescent cell targeting in mice.

We discovered that the abundance of IL-23R, CCL5, and other proteins showing age-dependent increases in circulation were reduced by senotherapeutic agents. CA13 decreased in aged plasma, and senolytics restored this factor toward youthful levels. In secretory tissues, gene expression of Il23r and Ccl5 coincided with expression of senescence markers and aged plasma protein abundance in vivo, and these factors were significantly upregulated and secreted by senescent cells in vitro. Our results suggest that senescent cells in aged kidney, liver, and spleen are viable sources of these aging biomarkers in blood circulation. Among the drugs tested, venetoclax suppressed age-related changes in the greatest number of circulating and tissue biomarkers in aged mice. In human plasma, we discovered that IL-23R abundance increased with age in both women and men.

Epigenetic clocks assess data derived from a bulk set of cells derived from tissues. This will be a mix of cells of different types and subpopulations, and thus some portion of age-related changes might be due to shifts in the relative numbers of these cell types. This has already been explored to some degree in the context of white blood cells in a blood sample, and the better commercial epigenetic age assays are now somewhat improved for that exploration. Here researchers discuss the problem more generally, and demonstrate that separating out cell types can be expected to improve epigenetic clocks and age assessment for any tissue.

The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution.

Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock's accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer's disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally.

Link: https://doi.org/10.18632/aging.206184

Cells react to the state of the extracellular matrix that they reside in. Changes to the molecules of the extracellular matrix do take place with age, and as a whole this aspect of aging is comparatively poorly studied and understood. Researchers here characterize one specific molecular alteration of extracellular matrix molecules that is found in aged lung tissue, show that it changes cell behavior for the worse via interaction with the cell surface, and demonstrate that an immunotherapy approach to remove these problem molecules reduces age-related pathology in an animal model of lung disease.

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable. IsoAsp-Gly-Arg (IsoDGR) modification has previously been observed in structural proteins such as fibronectin, laminin, tenascin C, and several other extracellular matrix (ECM) constituents of human arteries, leading to increased leukocyte infiltration of coronary vessels. These ECM proteins are also essential components of human lungs, which consist of a complex anatomy of fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), glycosaminoglycans (heparin, hyaluronic acid), and proteoglycans (perlecan, versican). These long-lived lung proteins are particularly susceptible to isoDGR accumulation, potentially triggering macrophage infiltration and expression of pro-inflammatory cytokines. Indeed, isoDGR structurally mimics the Arg-Gly-Asp (RGD) integrin binding motif, and may therefore mediate leukocyte recruitment to induce pulmonary inflammaging, but it is unknown whether this motif drives age-linked lung diseases such as fibrosis and emphysema

We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b+ macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo.

Link: https://doi.org/10.1111/acel.14425

Evidence points to increased autophagy as an important factor in many of the interventions that slow aging to extend life in short-lived laboratory species such as flies, worms, and mice. Autophagy is a collection of cellular maintenance processes responsible for clearing out excess and damaged structures in the cell, transporting them to a lysosome for disassembly. In principle, fewer damaged components leads to improved function across the board, and thus a greater resilience to the damage and dysfunction of aging.

Mild stresses placed on cells provoke greater autophagy. These include transient lack of nutrients, heat, cold, and excess oxidative molecules produced by mitochondria during periods of high energy demand, such as during exercise. The biochemistry of autophagy in longer-lived mammalian species such as our own in response to these interventions is very similar, at least where the data exists to make the comparison, such as for exercise and calorie restriction. Nonetheless, life span in longer-lived species changes little in response to greater autophagy: a calorie restricted mouse can live as much as 40% longer, but that certainly isn't true for humans.

Exercise-driven cellular autophagy: A bridge to systematic wellness

Among various interventions, physical exercise is recognized as a structured, intentional form of physical activity that enhances physical fitness, prevents diseases, and aids in recovery. Despite extensive research on its systemic benefits, the molecular mechanisms underlying exercise-induced health improvements remain incompletely understood, particularly regarding its impact on cellular processes across organ systems. One such cellular process is autophagy, a conserved metabolic pathway that maintains cellular homeostasis by degrading and recycling intracellular components. Autophagy is critical for cellular survival, development, and differentiation, as well as for mitigating diseases and maintaining health. Dysregulated autophagy is implicated in various pathological conditions, including neurodegenerative diseases, cancer, and metabolic disorders, highlighting its therapeutic potential.

Autophagy is indispensable for maintaining cellular health and is often impaired in systemic diseases. Interestingly, physical exercise-a macroscopic, non-pharmacological intervention-has been shown to activate autophagy, indicating a potentially critical link between these two processes. While numerous studies have independently explored the benefits of exercise and the mechanisms of autophagy, a comprehensive understanding of how exercise-induced autophagy contributes to systemic health and disease recovery is still lacking. Specifically, the molecular basis by which exercise modulates autophagic flux across different tissues and its implications for treating systemic diseases remains an area of limited clarity.

This review aims to address this knowledge gap by synthesizing current evidence on the role of exercise-induced autophagy in promoting health and mitigating disease. We will focus on the molecular mechanisms by which exercise regulates autophagy, the tissue-specific impacts of this regulation, and the potential therapeutic applications of targeting autophagy activation through exercise.

Most epigenetic clocks are produced by applying machine learning techniques to DNA methylation data derived from immune cells in reference blood samples taken from individuals of various ages. A clock is just an algorithm based on the fraction of genomes in the sample that are methylated at a number of specific Cpg sites. It is not too surprising to find that these clocks produce a different result when used on epigenetic data from tissue samples instead of blood samples, or that different tissues produce different results. After all, not all cell types have the same epigenetic response to aging. Some groups are working towards universal clocks for multiple species and multiple tissues, trying to find commonalities. Meanwhile, the most well known clocks function poorly outside the context in which they were manufactured, blood samples.

DNA methylation (DNAm) data from human samples has been leveraged to develop "epigenetic clock" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types. For all samples, we generated DNAm clock estimates for 8 epigenetic clocks and characterized these tissue-specific clock estimates in terms of their distributions, correlations with chronological age, correlations of clock estimates between tissue types, and association with participant characteristics.

For each clock, the mean DNAm age estimate varied substantially across tissue types, and the mean values for the different clocks varied substantially within tissue types. For most clocks, the correlation with chronological age varied across tissue types, with blood often showing the strongest correlation. Each clock showed strong correlation across tissues, with some evidence of some residual correlation after adjusting for chronological age. This work demonstrates how differences in epigenetic aging among tissue types leads to clear differences in DNAm clock characteristics across tissue types. Tissue or cell-type specific epigenetic clocks are needed to optimize predictive performance of DNAm clocks in non-blood tissues and cell types.

Link: https://doi.org/10.18632/aging.206182

The aging of the immune system is clearly an important factor in degenerative aging as a whole. The immune system does much more than merely defend the body against pathogens and potentially harmful malfunctioning cells. It is also intimately involved in tissue maintenance, tissue functions, and regeneration from injury. All of this suffers when the immune system becomes more inflammatory and less capable with advancing age. As for all aspects of aging, there is more than enough available biological data relating to immune system function to build clocks that reflect biological age, the burden of damage and dysfunction leading to mortality.

Precisely assessing an individual's immune age is critical for developing targeted aging interventions. Although traditional methods for evaluating biological age, such as the use of cellular senescence markers and physiological indicators, have been widely applied, these methods inherently struggle to capture the full complexity of biological aging. We propose the concept of an 'immunosenescence clock' that evaluates immune system changes on the basis of changes in immune cell abundance and omics data (including transcriptome and proteome data), providing a complementary indicator for understanding age-related physiological transformations.

Rather than claiming to definitively measure biological age, this approach can be divided into a biological age prediction clock and a mortality prediction clock. The main function of the biological age prediction clock is to reflect the physiological state through the transcriptome data of peripheral blood mononuclear cells (PBMCs), whereas the mortality prediction clock emphasizes the ability to identify people at high risk of mortality and disease. We hereby present nearly all of the immunosenescence clocks developed to date, as well as their functional differences. Critically, we explicitly acknowledge that no single diagnostic test can exhaustively capture the intricate changes associated with biological aging. Furthermore, as these biological functions are based on the acceleration or delay of immunosenescence, we also summarize the factors that accelerate immunosenescence and the methods for delaying it.

A deep understanding of the regulatory mechanisms of immunosenescence can help establish more accurate immune-age models, providing support for personalized longevity interventions and improving quality of life in old age.

Link: https://doi.org/10.1016/j.arr.2024.102653

In principle one could develop rejuvenation therapies without a way to measure the overall state of biological age. Each of the underlying causes of aging is measurable today: senescent cell burden, mitochondrial dysfunction, presence of amyloids, and so forth. Therapies can be assessed for efficacy in terms of the degree to which they repair the specific forms of cell and tissue damage that they are intended to repair. That doesn't tell us how much of an effect any given therapy will have on life span, however. It remains the case that while the causes of aging are well discussed, their importance relative to one another remains unknown.

It seems plausible that any approach to rejuvenation therapy will receive comparatively little support in today's environment without some measure of success beyond repair of a form of damage, meaning a measure of the degree to which the future risk of age-related disease and mortality is reduced. Unfortunately, that measure is expensive and slow to achieve via the old-fashioned approach of waiting to see what happens following treatment. Hence the strong focus on the development of aging clocks, technologies that may lead to a consensus method of quickly measuring biological age, and thus the effects of a potential rejuvenation therapy.

Critical review of aging clocks and factors that may influence the pace of aging

Aging research has delineated the aging process by classifying two separate but interconnected mechanisms: intrinsic and extrinsic aging. Intrinsic aging describes changes in biological hallmarks including cellular and molecular changes, genetics, and hormonal changes that have been described to occur naturally over time. Extrinsic aging, however, is regulated by exposure to environmental stressors, dietary habits, oxidative stress, and other factors that accelerate physiologic aging. Traditionally, aging has been quantified by chronological age, which is the exact number of years an individual has lived. However, chronological age does not fully capture the heterogeneity of the aging process, excluding many extrinsic factors that contribute to aging.

Subsequently, the calculation of biological age, which aims to account for interindividual variations in aging rate, has become a topic of interest in aging research. Aging clock models are tools that utilize various modeling approaches to estimate chronological or biological age. Moreover, aging clock models can estimate the rate of aging (ΔAge), otherwise known as the difference between model-predicted biological age and chronological age. Positive differences between model-predicted biological age and chronological age indicate accelerated aging whereas a negative difference indicates decelerated aging. If the calculated ΔAge exceeds the mean absolute error (MAE) of the aging rate estimation, these individuals can be determined to be fast or slow agers.

Aging clocks models may utilize any hallmark changes that occur because of aging, and these may include epigenetic changes, telomere length, genomic stability, altered intercellular communication, chronic inflammation, and gut microbiome dysbiosis, among others. Notably, some of the first aging clock models include the Horvath clock and Hannum clock, which are both epigenetic clocks modeled after changes in DNA methylation patterns and varying cytosine phosphate guanine (CpG) sites across the genome. Several aging clock models have emerged since then, varying from microbiome-based clocks to proteomic clocks. Recent advancements in the development of large databases, omics technologies, and deep learning models have accelerated the creation of aging clock predictions. Thus, this review aims to summarize the currently available aging clock models, with the goal of identifying existing and potential clinical applications.

Frailty is a state of chronic inflammation, immunosenescence, physical weakness, and reduced resilience to stresses. It is the outcome of a high burden of the cell and tissue damage of aging, and all of the downstream consequences of that damage. Frailty is well known to correlate with an increased mortality risk, and the study here is one of many to demonstrate this point. We might look on frailty as a pointer to the most severe issues in aging, a list of those problems that should be addressed with the highest priority, if possible. Certainly both immune dysfunction and loss of muscle mass and strength are well studied, with numerous therapeutic research and development programs underway at various stages.

This study aimed to explore the association of 3-year change in frailty index (FI) with risk of all-cause mortality in an older Chinese population. We analyzed the data of 4,969 participants from the Chinese Longitudinal Healthy Longevity Survey. The primary outcome was all-cause mortality, which was a binary variable and defined as completed data and censored data. Cox proportional-hazard models were used to assess the association of 3-year change in FI with risk of all-cause mortality.

During a median of 4.08 years of follow-up, deaths were observed in 1,388 participants. We observed a 2.27-fold higher risk of all-cause mortality with increase in FI ≥ 0.045 versus change in FI < 0.015 (hazard ratio = 2.27). Similar significant associations were observed in the subgroup analyses by age, sex, and residence at baseline. Additionally, a nonlinear dose-response association of 3-year change in FI with risk of all-cause mortality was observed. In conclusion, excessive increase in FI was positively associated with an increased risk for all-cause mortality. Approaches to reducing FI may be of great significance in improving the health of older Chinese individuals.

Link: https://doi.org/10.1186/s12877-024-05639-1

In the northern hemisphere, mortality increases in the winter. This is in large part because influenza is a winter phenomenon, and old people are vulnerable to infection and downstream consequences of infection. Cold weather provides a number of opportunities beyond infection for additional stresses to be placed on an aged body, however. An important characteristic of the frailty of old age is an inability to resist stresses that younger people would take in their stride, instead tipping over into the downward spiral to mortality. Researchers here survey the seasonality of human mortality, quantifying the overall size of the effect.

Seasonal fluctuations in mortality affect annual life expectancy at birth (e0). Nevertheless, evidence on the impact of seasonal mortality on longevity is very limited and mainly restricted to assessing season-specific mortality levels due to shocks (e.g., heatwaves and influenza epidemics). We investigated the influence of seasonality in mortality on life expectancy levels and temporal trends across 20 European countries during 2000-2019. We used harmonised weekly population-level mortality data from the Human Mortality Database. Seasonal contributions to life expectancy at birth and age 65, by sex, were estimated using the excess mortality approach and decomposition analysis. Time-series analysis was used to evaluate the impact on long-term mortality trends.

Seasonal mortality had a substantial but stable impact on e0 between 2000 and 2019. On average, we found an annual reduction in life expectancy due to seasonal excess mortality of 1.14 years for males and 0.80 years for females. Deaths in the elderly population (65+) were the main driver of this impact: around 70% and 90% of these reductions in life expectancy were attributable to older ages. Excess mortality in winter had the strongest impact on annual life expectancy, especially in Portugal and Bulgaria (around 0.8-year loss on e0). The study revealed significant cross-country variations in contributions of seasonal mortality. The most pronounced effects were observed in winter months and at older ages. These findings underscore the need for timely and targeted public health interventions to mitigate excess seasonal mortality.

Link: https://doi.org/10.1136/jech-2024-223050

Senescent cells are created constantly throughout life, but are rapidly removed by the immune system. Only in later life does the efficiency of immune clearance falter to allow senescent cells to accumulate. Lingering senescent cells cause harm in proportion to their numbers, secreting inflammatory signals that disrupt tissue structure and function. Numerous approaches to the selective clearance of senescent cells exist, and numerous companies are developing senolytic therapies that should improve health in later life, turning back aspects of aging by removing the senescent cells that are actively maintaining a degraded state of tissue function.

Instead of clearing senescent cells via present methods that attack features of senescent cell biochemistry to force apoptosis, is it possible to address the age-related changes that cause slowed immune clearance? On the one hand there are many avenues of research and development that might restore some lost function in the aged immune system, and it remains to be seen as to how they will affect surveillance of senescent cells. On the other hand, it appears that senescent cells in older individuals are different from those in younger individuals in ways that hamper the immune system. In today's open access paper, researchers find that senescent cells expressing GD3 at their cell surface can evade the attention of natural killer cells of the innate immune system. Sabotaging this mechanism would aid in immune clearance of senescent cells in aged individuals.

A ganglioside-based immune checkpoint enables senescent cells to evade immunosurveillance during aging

Advancing age goes hand in hand with the increased susceptibility to develop diseases that lead to functional decline, loss of autonomy, and healthcare system saturation. Mechanistically, the accumulation of senescent cells (SnCs) in tissues emerges as a key driver of aging and age-associated diseases. Thus, according to the geroscience hypothesis, considerable efforts are being made to find senotherapeutic strategies that allow the elimination or modification of SnCs to prevent and simultaneously treat many age-related diseases. Different senolytic compounds target the SnC intrinsic property to resist apoptosis due to Bcl-2 family protein overexpression.

Despite the existence of immune pathways to eliminate them, some SnCs can be tolerated in tissues for decades, and how they can be tolerated by the immune system remains an open question. The mechanisms by which these SnCs evade T cell surveillance can depend on immune checkpoints such as PD-L1. However, how SnC cells can evade from innate immunity, such as natural killer (NK) cell killing, is still elusive. In the present study, we discovered that SnCs can gain an immune privilege when they express at their cell surface a high level of the ganglioside GD3, leading to the escape from natural killer (NK) cell killing. This is the case for a large panel of SnC types, which upregulate the ST8SIA1 gene encoding the enzyme synthesizing GD3. In contrast, oncogene-induced SnCs do not trigger ST8SIA1 expression, enabling their elimination by NK cells.

Moreover, we demonstrate that anti-GD3 immunotherapy in mice prevents the development of bleomycin-induced lung fibrosis and attenuates different types of age-related disorders: lung and liver fibrosis and osteoporosis. These findings reveal GD3 as a senescence immune checkpoint and as a promising target for anti-senescence therapy.

Mitochondria are the power plants of the cell, producing chemical energy store molecules used to power cell activities. Energy hungry tissues such as muscle and brain are particularly sensitive to differences in mitochondrial function. Here, researchers show in a human study population that better mitochondrial function in muscle tissue correlates with slower aging in many areas of the brain. Interestingly, this relationship occurs regardless of physical fitness, though it is true that any given individual can be expected to achieve better mitochondrial function through attaining a greater degree of physical fitness. Physical fitness is beneficial in many ways, but it is the improvement in mitochondrial function resulting from greater physical fitness that drives the relationship with brain aging noted here, not the fitness per se.

This longitudinal study demonstrates a significant relationship between skeletal muscle mitochondrial oxidative capacity and brain structural changes up to over a decade, emphasizing the strong connection between mitochondrial health and brain aging and neurodegeneration. By investigating two different neuroimaging modalities across multiple brain regions, we identified specific brain regions and connecting tracts that were related to mitochondrial oxidative capacity assessed in the skeletal muscle. These longitudinal findings provide mechanistic insights into the connection between muscle bioenergetics and brain aging and lay a foundation for future research on mitochondrial bioenergetics in the brain.

One potential mechanism is that muscle mitochondrial function indicates general mitochondrial health and that muscle mitochondria can be considered a proxy measure of mitochondrial health across multiple tissues, including the brain. Another possibility is that the measure of oxidative capacity captures general muscle health and that positive signaling through soluble molecules and/or microvesicles may act in neurotrophic signaling that promotes brain health. While skeletal muscle oxidative capacity is related to fitness, the longitudinal associations between skeletal muscle oxidative capacity and brain atrophy were independent of concurrent fitness levels. Longitudinal associations with microstructural change persisted after accounting for the fitness measure of 400-meter walk time but were attenuated after adjusting for VO2 max. This attenuation is not surprising as fitness and vascular factors are strongly associated with white matter microstructure.

Because of the observational nature of this study, the detected longitudinal associations may shed light on but do not prove a causal relationship. In addition, we cannot exclude that higher skeletal muscle oxidative capacity reflects in part the lifetime history of exercise and physical activity which may affect several aspects of brain health but may not be fully captured by the assessment of current fitness levels.

Link: https://doi.org/10.1038/s41467-024-55009-z

Numerous research groups are investigating the cellular biochemistry of highly regenerative species such as salamanders and zebrafish. The goal is to find the differences that ensure regrowth of lost tissue rather than the scarring that occurs in mammals. So far, many of these differences appear to involve the continued operation of processes of regulated growth that take place during embryonic development. It is hoped that some of these differences can form a practical basis for regenerative therapies that will allow the safe regrowth of loss limbs and organ tissues. The approach noted here appears promising, as it is just a difference in expression of a gene regulating chromatin structure, rather than a difference in protein structure and function between species. Engineering higher or lower expression of specific native genes is practical, but introducing novel proteins with different sequences into an adult organism is more challenging to achieve safely, as the immune system can react poorly.

In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program.

Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.

Link: https://doi.org/10.1038/s44161-024-00588-9