Battle Aging

Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging. The sooner these treatments arrive, the more lives will be saved. Find out how to help ».

As noted in today's open access paper, one can't just apply Yamanaka factors globally to obtain a good outcome. Some tissues react poorly. Thus researchers have focused initially on a few use cases in which it seems likely that there is a path to therapies at the end of the day, many of which are focused on neural tissue. That said, the work here involves direct injection of gene therapy vectors to specific areas of the brain, and thus is at the very least a lengthy delivery technology research and development program away from adoption. The primary challenge in the development of gene therapy is how to obtain selective delivery to specific areas of the body when direct injection is infeasible, expensive, or risky. There is no clear path ahead at this time for many of the relatively small and deeply internal tissues.

At the molecular level, gene expression studies in aging rodents have documented significant changes in hippocampal genes related to cholesterol synthesis, inflammation, transcription factors, neurogenesis, and synaptic plasticity. In the hippocampus of female rats, 210 genes have been reported to be differentially expressed in aged individuals compared to their young counterparts, with the majority being downregulated.

Yamanaka genes, along with other pluripotency genes, possess high therapeutic potential for treating the aged central nervous system affected by various neurodegenerative diseases. Recent results revealed that the Yamanaka genes display a dual behavior when expressed continuously in vivo, being regenerative when delivered via viral vectors but highly toxic when expressed in transgenic mice. Thus, it has been reported that delivery of the OSK genes by intravitreally injecting a regulatable adeno-associated viral vector type 2 (AAV2) expressing the polycistron OSK can reverse vision deficits in an experimental model of glaucoma in mice as well as in 11 months old mice showing age-related vison impairment. Fifteen months of continuous expression of the OSK genes in retinal ganglion cells (RGCs) induced neither pathological changes nor proliferation of RGCs. Young- and middle-aged mice injected intravenously with OSK-AAV2 for 15 months did not exhibit any adverse side effects. In contrast, DOX-induced expression of OSK genes in mice transgenic for OSK resulted in rapid weight loss and death, likely due to severe dysplasia in the digestive system.

Administering an adenovector to the hypothalamus of young female rats, which carries both the OSKM transcription factors and the green fluorescent protein (GFP) marker, has not only significantly decelerated the pace of reproductive aging but also tripled the fertility rates in 9-month-old females compared to those receiving a placebo vector. Notably, at 9 months of age, female rats are approaching the age of ovulatory cessation, which typically occurs at around 10 months. Inspired by the pioneering results achieved by a team employing OSK gene therapy in the retina of mice, we decided to conduct a medium-term 39-day OSKM gene therapy trial in another brain region: the hippocampus of aged rats. The main goal was to restore learning and spatial memory performance in this animal model. For comparison, we used control groups of similarly aged rats injected with a placebo adenovector.

The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation.

Rapamycin is arguably the best of the calorie restriction mimetic drugs so far tested in mice. It slows aging robustly in animal studies, and has been used in humans at much higher doses than the anti-aging dose (around 5mg once per week) for decades. Still, there is a lack of human trials conducted for the purposes of slowing aspects of aging. More trial data than the little that presently exists would increase the number of physicians willing to prescribe off-label for anti-aging purposes. The specific focus of the trial doesn't much matter so long as the researchers measure enough data to assemble biomarkers of aging and general health. So, for example, one might look at a recently launched study of gum disease in older patients, and the study noted here that is focused on ovarian aging. Both have the potential to produce data relevant to the general question of aging. There are a few more such studies beside these, either planned or in the early stages.

Research into repurposing the immunosuppressant rapamycin has been hailed a "paradigm shift" in how menopause is studied. The Validating Benefits of Rapamycin for Reproductive Aging Treatment (Vibrant) study is designed to measure whether the drug can slow ovaries ageing, thereby delaying menopause, extending fertility and reducing the risk of age-related diseases. The study, which will eventually include more than 1,000 women, now has 34 participants aged up to 35, with more women joining every day.

A clinical trial of rapamycin in humans has also been considered impossible because it would take decades to detect any longevity effects. Ovaries, however, age so quickly that change can be measured over six months. The level of rapamycin used is small: women are given 5mg a week for three months compared with the 13mg a day that transplant patients can be prescribed for years.

The gut microbiome influences long-term health. The balance of microbial populations shifts with age to become more harmful, certainly more inflammatory. While it is possible to produce sizable benefits to health via rejuvenation of the aged gut microbiome with simple approaches, such as fecal microbiota transplantation using a young donor, the future will clearly involve more of the application of biotechnology to the problem. If one can produce lasting change in the composition of the gut microbiome by delivering microbes in sufficient quantity, then why not deliver engineered versions of existing gut microbes that are altered to produce less inflammatory signaling or more beneficial metabolites?.

This was achieved using a non-replicative DNA vector, preventing maintenance and dissemination of the payload. We then leveraged this approach to edit several genes of therapeutic relevance in E. coli and Klebsiella pneumoniae strains in vitro and demonstrate in situ editing of a gene involved in the production of curli in a pathogenic E. Our work demonstrates the feasibility of modifying bacteria directly in the gut, offering a new avenue to investigate the function of bacterial genes and opening the door to the design of new microbiome-targeted therapies.

It has been a question for some time as to whether immune cells expressing p16 and β-galactosidase, markers of cellular senescence, are in fact all or even majority senescent. Macrophages, for example, can certainly express these proteins without entering a senescent state. Some assays of cellular senescence and associations with disease published in past years are thus likely reflective of both (a) the burden of senescence, but also (b) other responses to aging or processes of aging taking place in immune cell populations, particularly those resident in tissues.

With that in mind, today's open access paper is an interesting exploration of what exactly it is that these maybe-senescent p16 and β-galactosidase expressing immune cells might be doing in the aged body. The authors draw in the concept of disease tolerance, which might be thought of as covering all of the ways in which cells might act, individually or in collaboration, to reduce the impact of infectious disease without killing the pathogens involved. It is not what one might think of the immune system being involved in, but nonetheless, that may be an evolved role for p16 and β-galactosidase expressing immune cells.

Does this mean that it is a bad idea to clear a large fraction of the p16-expressing or β-galactosidase-expressing cells in the body? Probably not, provided one restricts clearance to a short period of time, and avoids doing it while the patient is infected or injured. It has always been known that senescent cells do have useful roles when present for the short-term, including wound healing, suppression of potentially cancerous cells, and so forth. The problem in aging is that there are too many lingering senescent cells, to the point at which any benefit is buried by the downside of constant pro-inflammatory signaling. Getting rid of the excess in a short period of time should allow the useful processes to pick up again.

Substantial experimental evidence suggests that the accumulation of senescent cells is an important factor in age-related tissue deterioration as it is associated with the production of different molecules capable of restructuring the extracellular matrix, modifying the behavior of neighboring cells and systemically affecting the activity of the immune system. Despite these deleterious functions of senescent cells in the aging process, accumulating evidence supports cellular heterogeneity among p16High cells with some mediating important homeostatic functions that have been identified during embryonic development as well as in adult skin, liver and lung. This suggests that depending on the context, p16High senescent cells could be either beneficial or detrimental. What defines either group remains however largely unknown.

The development of different genetic mouse models is now facilitating the further identification and characterization of p16High cells in vivo. Among the different p16High subtypes, cells of the immune system, including T cells and macrophages, have been identified and further analysis revealed that some express additional markers of senescence such as enhanced senescence-associated β-galactosidase (SA-β-gal) activity and DNA damage. Furthermore, the frequency of such cells increases significantly in animals during natural and accelerated aging, which may highlights their potential importance. On the other hand, a modest or even transient activation of p16, as well as excessive lysosomal activity (and thus higher SA-β-gal activity) in phagocytic cells such as macrophages has been observed under different conditions. Whether such activation indeed reflects classical pathways of senescence activation is unclear.

In our current study, we used a genetic mouse model to trace cells with high expression of p16 in vivo. We found that the p16High program was activated during aging not only in long-lived macrophages and T cells, but in all the immune subsets analyzed. Our detailed analysis of T cells and tissue-resident macrophages as well as the use of a genetic model for selective ablation of p16High cells, allowed us to determine that p16High immune cells play an important regulatory functions in vivo. These functions were further critical for animal survival after severe inflammation and tissue damage. While the ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens, evidence indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we argue that induction of p16High immune cells is a key mechanism in establishing disease tolerance.

Ever-shifting epigenetic marks on the genome determine its structure in the cell nucleus, and thus which portions of the genome are accessible to the machinery of gene expression, and thus which proteins are produced at a given time. This epigenetic regulation of gene expression changes in characteristic ways with age, and many of those alterations are clearly maladaptive. Hence the present interest in epigenetic reprogramming, in which researchers adapt some of the processes that take place during embryonic development in order to restore a youthful epigenetic state to adult cells. It is very much a work in progress, but early results in animal studies are promising.

Neurons undergo pronounced alterations in morphology and function throughout the lifespan, and these have been related to disturbed neuronal signaling and impaired information processing in the aged brain. The function of different neuron types in multiple brain areas is affected by aging, with the hippocampus and prefrontal cortex - both brain regions with key roles in memory storage and cognitive flexibility - being particularly compromised.

Since neurons are post-mitotic and mostly generated during early development, they represent one of the oldest cell types in the body. Therefore, to preserve their function throughout life, neurons are dependent on the long-term maintenance of molecular programs that define their neuronal identity and enable activity-induced plasticity in response to environmental cues. Yet, multiple studies have reported impairments in neuron-specific gene expression programs in the aging brain, including alterations in transcription, RNA processing, and protein levels, which have been linked to neuronal dysfunction. The long-term maintenance of neuronal gene expression programs critically depends on the epigenetic machinery, and accumulating evidence suggests impairments of epigenetic regulation as cell-intrinsic drivers of aging in neurons.

Intriguingly, recent studies suggest that neuronal epigenetic aging can be slowed down or reversed by rejuvenating interventions that are known to counteract age-related impairments in brain function, thus opening the field for therapeutic anti-aging strategies. Interventions shown to be effective include changes to lifestyle (such as exercise, environmental enrichment, and caloric restriction), the transfer of young blood factors or cellular reprogramming, among others. The malleability of the neuronal epigenome during aging suggests that it can be targeted to prevent epigenetic aging or even restore a youthful epigenetic state in aged neurons.

The influence of the gut microbiome on the long-term trajectory of health is a popular topic these days. Tools for assessing the microbial composition of the gut microbiome are accurate and cost little, and variance in the relative sizes of microbial populations between individuals and across a life span are increasingly correlated with effects on health, disease, and the pace of aging. Of particular interest are the ways in which the gut microbiome may be affecting the operation of the brain, such as via the generation of harmful inflammatory signaling, or the production of metabolites such as butyrate that can influence neurogenesis. Here, researchers focus specifically on connections between the gut microbiome and the supporting astrocyte cells of the brain, known to become dysfunction with age.

Over the past decade, the roles of the intestinal microbiota in regulating the gut-brain axis and its involvement in the pathophysiology of brain aging have become increasingly emphasized. A previous study has shown that the gut microbiota is an important upstream factor in astrocyte activation, which is closely associated with neuroinflammation and neurodegeneration. Thus, a deeper comprehension of the roles and mechanisms of the gut microbiota-astrocyte axis in age-related cognitive decline is becoming ever more necessary and meaningful. This review aims to elucidate and summarize the unique changes to gut microbiomes seen during the process of aging, alterations in the shape and function of astrocytes within the aging brain, and potential mechanisms, such as the vagus nerve, immune responses, the circadian rhythm, and microbial metabolites, by which gut microbiomes influence cognitive function by impacting CNS astrocyte activity. In this way, we aim to provide new insights into therapeutic avenues for age-related cognitive decline.

Polyadenylation occurs during the creation of messenger RNA (mRNA). It is one part of the complex processes of transcription of the DNA sequence for a gene and assembly of the resulting RNA molecule. In the polyadenylation process, a tail of repeated adenine bases - called the poly(A) tail - is appended to the mRNA molecule. This protects the mRNA from degradation once it has left the nucleus, and also helps in other ways with the process of translation, in which the mRNA molecule is used as a blueprint by a ribosome to assemble protein molecules from amino acids. Changes in the length of the mRNA tail will affect levels of protein production, and thus the behavior of cells.

In today's open access paper, researchers report on their efforts to discover novel age-related changes in the nematode worm species Caenorhabditis elegans via extensive single cell sequencing of the transcriptome. This led them to uncover differences in the polyadenylation process (a) over the course of aging, and (b) between short-lived and long-lived nematode lineages. This age-related change in polyadenylation acts to reduce the pace of production of many proteins, which likely has many complex downstream effects, while longer-lived nematodes are somewhat resistant to this change in polyadenylation. Can this be dysfunction be rescued by a comparatively simple set of changes? Perhaps, as polyadenylation is regulated by a proteins that might be upregulated or downregulated, but it is likely a lengthy road from here to that sort of intervention.

Although multiple pro-longevity strategies have been discovered in multicellular organisms ranging from Caenorhabditis elegans to mice, whether and how these strategies slow aging of different tissues in distinct manners are yet to be determined. In recent years, single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq) have proven to be effective ways to systemically profile transcriptomes at single-cell resolution and have facilitated the discovery of cell-type-specific transcriptomic signatures in different tissues.

In this study, we used snRNA-seq transcriptomic profiling of different somatic cell and germ cell types to build an adult cell atlas. Using snRNA-seq data from wild-type (WT) adults at different ages, we generated tissue-specific transcriptomic aging clocks as well as germ cell differentiation trajectory maps to assess how aging affects the function of different cell types. We also revealed age-associated, tissue-specific transcriptomic changes associated with three different pro-longevity mechanisms. Furthermore, we profiled pre-mRNA alternative polyadenylation (APA) at the genome level in different cell types at different ages and systemically discovered APA events with tissue-specific patterns and how age-associated APA changes in different tissues are attenuated by those pro-longevity mechanisms.

APA plays a crucial role in the control of mRNA metabolism, gene regulation and protein diversification51. Our study provides, to our knowledge, the first systematic profiling of APA changes at the whole transcriptome level. Interestingly, APA events exhibit tissue-specific distribution, undergo significant changes during aging and can be differentially regulated by different pro-longevity mechanisms. We discovered that, during aging, all cell types shift their APA preference toward the distal site, and this shifted preference is suppressed in the long-lived strains. Previous studies revealed that the usage of the distal APA site is inversely correlated with the level of core polyadenylation factors.

Additionally, the increased usage of distal APA sites may lead to longer 3′ UTRs, which are associated with mRNA instability. Based on our findings, we speculate that, with aging, the level of core polyadenylation factors may decrease and the length of 3′ UTRs may increase, potentially resulting in declines in translational efficiency. Thus, suppressing the distal APA usage in the long-lived strains may help improve protein outputs, contributing to their longevity effects.

We identified 1,925 records in our initial search, of which five eligible systematic reviews were identified. Within these systematic reviews, we identified 71 potentially eligible primary papers, of which 27 were included in our analysis. 13 (48%) of 27 primary papers reported change in prevalence of dementia, ten (37%) reported change in incidence of dementia, and four (15%) reported change in both incidence and prevalence of dementia. Studies reporting change in dementia incidence over time in Europe (n=5) and the USA (n=5) consistently reported a declining incidence in dementia. One study from Japan reported an increase in dementia prevalence and incidence and a stable incidence was reported in one study from Nigeria.

Overall, across studies, the PAFs for less education or smoking, or both, generally declined over time, whereas PAFs for obesity, hypertension, and diabetes generally increased. The decrease in PAFs for less education and smoking was associated with a decline in the incidence of dementia in the Framingham study (Framingham, MA, USA, 1997-2013), the only study with sufficient data to allow analysis.

The characteristic loss of muscle mass and strength that occurs with age leads to sarcopenia and frailty. While a few companies are targeting this age-related muscle loss via development of small molecule drugs, the recent history of this part of the field is not encouraging. None of the attempted approaches have yet improved on exercise. That may well be due to a failure to specifically target underlying mechanisms that drive degenerative aging, projects instead relying on the sort of adjustments to metabolism that are discussed in the paper referenced here, but only time will tell.

A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy.

The use of hormone replacement and myostatin-based therapies in clinical trials - aimed at promoting muscle hypertrophy - has not resulted in notable advancements in muscle strength or functional performance. The decline in sex hormones that occurs with aging is closely tied to the development of sarcopenia. However, the potential adverse effects of sex hormone replacement therapy outweigh its modest advantages in mitigating muscle aging. There is no conclusive association between circulating myostatin level and muscle aging, and myostatin-based therapy does not affect muscle aging.

While effective in promoting muscle growth, hypertrophic signaling compromises muscle protein quality control, exacerbating age-related muscle dysfunction. An alternative intervention to refine mechanistic target of rapamycin (mTOR) functions is proposed to benefit muscle health in the elderly. Both hormone replacement and myostatin-based therapies stimulate muscle growth by activating mTORC1, which controls growth by responding to nutrient availability and should be active only when nutrients are present. Yet chronic activation of mTORC1 in skeletal muscle accelerates sarcopenia development in mice. The crucial question is whether the interventions focused on increasing muscle size through mTORC1 will truly be beneficial in addressing muscle aging in humans, given that mTORC1 insensitivity is frequently seen in aged individuals.

Adoptive cell therapies involve introducing immune cells to attack a specific issue in the body, most often cancer. The earliest forms of adoptive cell therapy used immune cells from another individual, but more modern approaches use a patient's own cells, expanded in culture and potentially engineered in various ways. Think of chimeric antigen receptor T cell (CAR-T) therapies, for example. Both T cells and natural killer (NK) cells have been employed as a basis for adoptive cell therapies targeted at cancer.

In today's open access paper, researchers consider another potential use for adoptive NK cell therapy, as a way to produce lasting clearance of senescent cells in aged tissues. It is clear that NK cells, along with several other immune cell types, are involved in the normal processes of destruction of senescent cells as they show up in the body. Unfortunately, this immune mediated clearance of senescent cells slows down with advancing age, allowing the build up of lingering senescent cells throughout the body. Senescent cells produce signaling that is useful under various circumstances, such as suppression of potentially cancerous damage and coordination in wound healing, but when sustained for the long term becomes highly disruptive to tissue structure and function.

Researchers have already demonstrated that CAR-T therapies can be adapted to target senescent cells. It is plausible that NK cell therapies can also serve this purpose. The question is whether the cost is worth it, when other forms of senolytic therapy that are capable of training the immune system to more aggressively attack senescent cells, including the Deciduous Therapeutics approach, are far cheaper. The primary issue with adoptive cell therapies at the present time is their high cost, an unavoidable outcome of any therapy that requires weeks or months of effort to grow, engineer, and quality control large numbers of cells from a patient sample. That doesn't compete well with the need to treat every older individual on some intermittent, recurring basis.

As the global population ages, the prevalence of associated diseases becomes increasingly apparent. The pursuit of healthy aging, characterized by heightened resistance to lethal diseases, is the cornerstone of preventive medicine. The aging process is a complex process involving cellular senescence and inflammation, with the immune system playing a pivotal role in managing these aspects. Timely clearance of senescent cells (SNCs) is central to maintaining tissue and organismal homeostasis. Unfortunately, immunosenescence, a progressively dysregulated immune state with age, fails to eliminate SNCs, leading to their accumulation. This often coincides with the release of senescence-associated secretory phenotypes (SASPs), inhibiting immunity and increasing vulnerability to aging-associated diseases (AADs).

Consequently, targeting immunosenescence and SNCs emerges as a crucial therapeutic strategy to preserve and extend healthy aging. While adaptive immunity has traditionally taken center stage in immunogerontological studies, growing evidence underscores the substantial impact of innate immunity in AADs. Natural killer (NK) cells, integral to the innate immune system, uniquely identify and eliminate aberrant cells such as tumor cells and virus-infected cells. Moreover, NK cells promptly address SNCs, and coordinate with other immune components through cytokine and chemokine production to surveil and eliminate cancer cells. Although whether the same occurs against SNCs remains to be determined.

Evidence from healthy elderly individuals, especially those exhibiting physical fitness, independence in daily activities, or adequate cognitive function, the number and function of NK cells are highly preserved. Conversely, diminished NK cell activity in elderly individuals is associated with disorders such as atherosclerosis and an elevated risk of mortality. Accordingly, preserving NK cell function during aging is deemed crucial for healthy aging and longevity. Alternatively, NK-cell-based therapies, notably adoptive NK cell therapy, aligning with their established role in cancer and viral infection treatments, show promise in rejuvenating immunosenescence, eliminating SNCs and alleviating SASPs, that lead to AADs.

The practice of calorie restriction, reducing calorie intake by up to 40% while still obtaining a sufficient level of micronutrients necessary to good health, is well demonstrated to slow aging. It slows near all aspects of aging and progression of near all age-related conditions, and so the literature is packed with papers that investigate just one of those line items. Here, the focus is on loss of bone mineral density with age, a phenomenon that leads to osteoporosis and eventual fracture and incapacity. This is one of the few age-related conditions for which there is some debate over whether moderate or greater calorie restriction is a net benefit, based on apparently contradictory animal data. My impression of the literature, reinforced here, is that the weight of evidence leans towards calorie restriction as a benefit in this matter.

Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardiometabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure, and its endocrine profile in the context of aging.

Young and aged male C57Bl6/J mice were subjected to CR for 8 weeks and compared to age-matched littermates with free food access. CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice.

Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

The measurement of life span is self-evident and obvious, but is little consensus on how to measure health span, the length of life spent in good health. Good health is like art, we know it when we see it, but that isn't helpful when trying to compare the effects of interventions where the studies were conducted by different researchers with different ideas as what constitutes good health in an older individual. This issue exists for both human and animal studies, and the lack of consistency makes it hard to make comparisons based on the existing literature on the topic. Researchers are starting to propose rigorous definitions of health span, but it seems that we stand some distance removed from any great agreement as to which of these definitions is the one to adopt as a standard.

Unlike lifespan, which has a universal definition, there is no consensus on the definition of health span. Previous research has suggested characterizing healthy aging in five domains: physical capability, cognitive function, physiological and musculoskeletal, endocrine, and immune functions. For practical purposes, health span typically refers to the period of life spent in good health, free from the chronic diseases and disabilities of aging. Studies aiming to evaluate the effects of interventions on health span are challenging due to the need for long follow-up lengths and large sample sizes of healthy individuals to observe the outcomes of interest. Thus, developing surrogate biomarkers that can predict health span is crucial for improving the feasibility of clinical trials to test interventions to prolong health span and lifespan.

Composite biomarkers incorporating multiple measures are more robust in predicting age-related outcomes than single biomarkers. Several composite biomarkers for predicting lifespan or mortality have been developed using clinical biomarkers or omics data. However, to date, no composite biomarker measures have been developed based on a healthspan definition. To mitigate this gap, we developed a proteomics-based healthspan biomarker (health span proteomic score, HPS) using chronological age and expression data of 2,920 proteins at the UK Biobank baseline/recruitment (2006-2010).

A lower HPS was associated with higher mortality risk and several age-related conditions, such as COPD, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to chronological age and biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. Our findings demonstrate the validity of HPS, making it a valuable tool for assessing health span and as a potential surrogate marker in gero science-guided studies.

Amidst all of this, it is perhaps worth considering whether finding out why centenarians are so long-lived is actually worth all of the effort. Centenarians are frail, a shadow of their younger selves, and exhibit a sizable mortality rate. Is this really a desirable state to aim for? The research community has a very good list of the causative processes of degenerative aging, the forms of molecular damage that accumulate in aged bodies to produce dysfunction. It requires exactly zero further knowledge of centenarian biochemistry to be able put a great deal of effort into the development of potential rejuvenation therapies that are capable of repairing this damage. The end result of successful, comprehensive rejuvenation via damage repair will not be people who are as damaged and frail as today's centenarians.

Diverse factors have been associated with healthy or unhealthy aging such as demographic factors; pro sociality level, physical and organic health status, mental health, lifestyle factors, and genetics. This converges in the concept of biological aging (BA), defined as the set of processes that cause organ deterioration over time. BA depends on the complex interaction of these factors, which can lead to a heterogeneous aging process across multiple organic systems, and correlate with a specific survival time and health or disease phenotype even in advanced ages. To deeply understand the mechanisms associated with aging and to identify potential targets for intervention to control or delay BA and the onset of diseases, it is necessary to study successful BA models. These models reflect phenotypes that are resistant to external stress factors with a favorable organic response. Centenarians, individuals with a chronological age (CA; defined as the number of years an individual has lived) equal to or greater than 100 years, constitute one such model of successful aging.

Currently, there is a significant knowledge gap from the translational perspective due to the evolutionary and exhaustive nature of aging research, which requires robust and reproducible omics studies on populations (specially in centenarians). These studies would aid in understanding precisely how modifiable and nonmodifiable factors impact the organic evolution of centenarians. Cellular senescence, epigenetic clocks, and alterations in stem cells, are some of the cellular and molecular processes that could theoretically reflect cellular proteo dynamics, adaptation to aging, and the development of health phenotypes and prognosis during longevity. Having specific data on these mechanisms could facilitate the identification of aging biomarkers for cells, tissues, organs, or diseases, and predict the onset of age-related chronic diseases. However, there are not enough, studies to corroborate these hypotheses based on centenarians as a model of successful aging. Therefore, evidence regarding possible interventions to delay aging and prevent the onset of age-related chronic diseases into extreme ages remains weak and speculative.

The gut microbiota (GM) has been described as a biological and metabolic regulator of various organs and diseases. Age and diet, determinants in aging, are two factors directly related to the establishment and modification of the composition of the GM. To date, little discussion has taken place regarding the specific changes that occur in the long-lived population, which allow the establishment of an antioxidant system with characteristics similar to those of a young population, as a result of successful evolutionary adaptation. Although the specific mechanisms are unknown, this may possibly be one of the strongest reasons influencing life expectancy and healthy lifespan during aging.

To understand the possible impact generated by the GM, its changes, and the probable causes for successful aging, the aim of this review was to synthesize evidence on the role of the GM as a potential protective factor for achieving extreme longevity, using its relationship with centenarians. Evidence suggests that there are significant changes in the composition of the GM of centenarians, compared to other age groups, which could be associated with specific phenotypes of healthy aging, and be determinants in extreme longevity. However, numerous factors condition the establishment of the GM over time. The origin of the data is limited to certain countries with some blue zones. This field should be extensively studied in regions lacking data and determine the possible specific causal association between genera and species of microorganisms, and extreme longevity.

Growing evidence suggests that the ageing process significantly impacts leukocyte trafficking dynamics during inflammation, thereby compromising protective immunity. We have previously reported that ageing increases homeostatic leukocyte trafficking to the peritoneal cavity in mice through pro-inflammatory mediators and enhanced vascular permeability. Whilst ageing increases neutrophil and monocyte trafficking in response to peritonitis, patterns of lymphocyte trafficking are still unknown in this model.

Here, we investigated how ageing changes leukocyte trafficking dynamics and the impact of a novel immunopeptide (PEPITEM) has on this using an inflammation model of zymosan-induced peritonitis in young (3-month) and aged (21-month) male mice. Zymosan-induced peritonitis typically represents a simplified model of the disease, focusing primarily on the early inflammatory events. It may not adequately capture the later stages of human peritonitis development, including tissue damage and organ dysfunction. Nonetheless, it remains a highly reproducible and robust model, characterised by significant recruitment of various immune cells.

The aging brain malfunctions in complex ways, giving rise to a range of poorly categorized end states beyond the most prevalent, well known neurodegenerative conditions. As an example of research in this part of the field, scientists here discuss a form of age-related memory loss that they call limbic-predominant amnestic neurodegenerative syndrome. Interestingly, this condition appears to be associated with TDP-43 pathology, a comparatively recently discovered form of harmful protein aggregation in the aging brain that is now known to contribute to some forms of neurodegeneration.

Researchers have established new criteria for a memory-loss syndrome in older adults that specifically impacts the brain's limbic system. It can often be mistaken for Alzheimer's disease. Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, progresses more slowly and has a better prognosis. Prior to the researchers developing clinical criteria the hallmarks of the syndrome could be confirmed only by examining brain tissue after a person's death. The proposed criteria provide a framework for neurologists and other experts to classify the condition in patients living with symptoms, offering a more precise diagnosis and potential treatments. They consider factors such as age, severity of memory impairment, brain scans, and biomarkers indicating the deposits of specific proteins in the brain.

"Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer's disease, and that is often how it's being thought of today. With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains." Without signs of Alzheimer's disease, the researchers looked at the involvement of one possible culprit - a buildup of a protein called TDP-43 in the limbic system that scientists have found in the autopsied brain tissue of older adults. Researchers have classified the build-up of these protein deposits as limbic-predominant age-related TDP-43 encephalopathy, or LATE. These protein deposits could be associated with the newly defined memory loss syndrome, but there are also other likely causes and more research is needed.

Home FAQ Fund Research Services Investing Therapies Newsletter Archives Press Room Resources About Fight Aging! Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging. The sooner these treatments arrive, the more lives will be saved. Find out how to help ».

Fight Aging! Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging. The sooner these treatments arrive, the more lives will be saved. 

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A number of groups have demonstrated that selectively exposing aged rodent tissues to expression of the Yamanaka factors - OCT4, SOX2, KLF4, and MYC (collectively OSKM) - can induce restoration of more youthful epigenetic patterns and gene expression, accompanied by restoration of tissue function. The Yamanaka factors were first explored as a way to replicate the process by which adult germline cells become embryonic stem cells at the outset of embryogenesis, leading to the now well established capacity to produce what are known as induced pluripotent stem cells from somatic cell samples. Importantly, this process doesn't just lead over time to a radical alteration of cell fate, but also quite rapidly rejuvenates epigenetic regulation of gene expression. As noted in today's open access paper, one can't just apply Yamanaka factors globally to obtain a good outcome. Some tissues react poorly. Thus researchers have focused initially on a few use cases in which it seems likely that there is a path to therapies at the end of the day, many of which are focused on neural tissue. That said, the work here involves direct injection of gene therapy vectors to specific areas of the brain, and thus is at the very least a lengthy delivery technology research and development program away from adoption. The primary challenge in the development of gene therapy is how to obtain selective delivery to specific areas of the body when direct injection is infeasible, expensive, or risky. There is no clear path ahead at this time for many of the relatively small and deeply internal tissues. Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy At the molecular level, gene expression studies in aging rodents have documented significant changes in hippocampal genes related to cholesterol synthesis, inflammation, transcription factors, neurogenesis, and synaptic plasticity. In the hippocampus of female rats, 210 genes have been reported to be differentially expressed in aged individuals compared to their young counterparts, with the majority being downregulated. /p> Yamanaka genes, along with other pluripotency genes, possess high therapeutic potential for treating the aged central nervous system affected by various neurodegenerative diseases. Recent results revealed that the Yamanaka genes display a dual behavior when expressed continuously in vivo, being regenerative when delivered via viral vectors but highly toxic when expressed in transgenic mice. Thus, it has been reported that delivery of the OSK genes by intravitreally injecting a regulatable adeno-associated viral vector type 2 (AAV2) expressing the polycistron OSK can reverse vision deficits in an experimental model of glaucoma in mice as well as in 11 months old mice showing age-related vison impairment. Fifteen months of continuous expression of the OSK genes in retinal ganglion cells (RGCs) induced neither pathological changes nor proliferation of RGCs. Young- and middle-aged mice injected intravenously with OSK-AAV2 for 15 months did not exhibit any adverse side effects. In contrast, DOX-induced expression of OSK genes in mice transgenic for OSK resulted in rapid weight loss and death, likely due to severe dysplasia in the digestive system. Administering an adenovector to the hypothalamus of young female rats, which carries both the OSKM transcription factors and the green fluorescent protein (GFP) marker, has not only significantly decelerated the pace of reproductive aging but also tripled the fertility rates in 9-month-old females compared to those receiving a placebo vector. Notably, at 9 months of age, female rats are approaching the age of ovulatory cessation, which typically occurs at around 10 months. Inspired by the pioneering results achieved by a team employing OSK gene therapy in the retina of mice, we decided to conduct a medium-term 39-day OSKM gene therapy trial in another brain region: the hippocampus of aged rats. The main goal was to restore learning and spatial memory performance in this animal model. For comparison, we used control groups of similarly aged rats injected with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation.

It has been a question for some time as to whether immune cells expressing p16 and β-galactosidase, markers of cellular senescence, are in fact all or even majority senescent. Macrophages, for example, can certainly express these proteins without entering a senescent state. Some assays of cellular senescence and associations with disease published in past years are thus likely reflective of both (a) the burden of senescence, but also (b) other responses to aging or processes of aging taking place in immune cell populations, particularly those resident in tissues. With that in mind, today's open access paper is an interesting exploration of what exactly it is that these maybe-senescent p16 and β-galactosidase expressing immune cells might be doing in the aged body. The authors draw in the concept of disease tolerance, which might be thought of as covering all of the ways in which cells might act, individually or in collaboration, to reduce the impact of infectious disease without killing the pathogens involved. It is not what one might think of the immune system being involved in, but nonetheless, that may be an evolved role for p16 and β-galactosidase expressing immune cells. Does this mean that it is a bad idea to clear a large fraction of the p16-expressing or β-galactosidase-expressing cells in the body? Probably not, provided one restricts clearance to a short period of time, and avoids doing it while the patient is infected or injured. It has always been known that senescent cells do have useful roles when present for the short-term, including wound healing, suppression of potentially cancerous cells, and so forth. The problem in aging is that there are too many lingering senescent cells, to the point at which any benefit is buried by the downside of constant pro-inflammatory signaling. Getting rid of the excess in a short period of time should allow the useful processes to pick up again. p16High immune cell - controlled disease tolerance as a broad defense and health span extending strategy Substantial experimental evidence suggests that the accumulation of senescent cells is an important factor in age-related tissue deterioration as it is associated with the production of different molecules capable of restructuring the extracellular matrix, modifying the behavior of neighboring cells and systemically affecting the activity of the immune system. Despite these deleterious functions of senescent cells in the aging process, accumulating evidence supports cellular heterogeneity among p16High cells with some mediating important homeostatic functions that have been identified during embryonic development as well as in adult skin, liver and lung. This suggests that depending on the context, p16High senescent cells could be either beneficial or detrimental. What defines either group remains however largely unknown. The development of different genetic mouse models is now facilitating the further identification and characterization of p16High cells in vivo. Among the different p16High subtypes, cells of the immune system, including T cells and macrophages, have been identified and further analysis revealed that some express additional markers of senescence such as enhanced senescence-associated β-galactosidase (SA-β-gal) activity and DNA damage. Furthermore, the frequency of such cells increases significantly in animals during natural and accelerated aging, which may highlights their potential importance. On the other hand, a modest or even transient activation of p16, as well as excessive lysosomal activity (and thus higher SA-β-gal activity) in phagocytic cells such as macrophages has been observed under different conditions. Whether such activation indeed reflects classical pathways of senescence activation is unclear. In our current study, we used a genetic mouse model to trace cells with high expression of p16 in vivo. We found that the p16 High program was activated during aging not only in long-lived macrophages and T cells, but in all the immune subsets analyzed. Our detailed analysis of T cells and tissue-resident macrophages as well as the use of a genetic model for selective ablation of p16H igh cells, allowed us to determine that p16 High immune cells play an important regulatory functions in vivo. These functions were further critical for animal survival after severe inflammation and tissue damage. While the ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens, evidence indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we argue that induction of p16High immune cells is a key mechanism in establishing disease tolerance.

Polyadenylation occurs during the creation of messenger RNA (mRNA). It is one part of the complex processes of transcription of the DNA sequence for a gene and assembly of the resulting RNA molecule. In the polyadenylation process, a tail of repeated adenine bases - called the poly(A) tail - is appended to the mRNA molecule. This protects the mRNA from degradation once it has left the nucleus, and also helps in other ways with the process of translation, in which the mRNA molecule is used as a blueprint by a ribosome to assemble protein molecules from amino acids. Changes in the length of the mRNA tail will affect levels of protein production, and thus the behavior of cells. In today's open access paper, researchers report on their efforts to discover novel age-related changes in the nematode worm species Caenorhabditis elegans via extensive single cell sequencing of the transcriptome. This led them to uncover differences in the polyadenylation process (a) over the course of aging, and (b) between short-lived and long-lived nematode lineages. This age-related change in polyadenylation acts to reduce the pace of production of many proteins, which likely has many complex downstream effects, while longer-lived nematodes are somewhat resistant to this change in polyadenylation. Can this be dysfunction be rescued by a comparatively simple set of changes? Perhaps, as polyadenylation is regulated by a proteins that might be upregulated or downregulated, but it is likely a lengthy road from here to that sort of intervention. Aging atlas reveals cell-type-specific effects of pro-longevity strategies Although multiple pro-longevity strategies have been discovered in multicellular organisms ranging from Caenorhabditis elegans to mice, whether and how these strategies slow aging of different tissues in distinct manners are yet to be determined. In recent years, single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq) have proven to be effective ways to systemically profile transcriptomes at single-cell resolution and have facilitated the discovery of cell-type-specific transcriptomic signatures in different tissues. In this study, we used snRNA-seq transcriptomic profiling of different somatic cell and germ cell types to build an adult cell atlas. Using snRNA-seq data from wild-type (WT) adults at different ages, we generated tissue-specific transcriptomic aging clocks as well as germ cell differentiation trajectory maps to assess how aging affects the function of different cell types. We also revealed age-associated, tissue-specific transcriptomic changes associated with three different pro-longevity mechanisms. Furthermore, we profiled pre-mRNA alternative polyadenylation (APA) at the genome level in different cell types at different ages and systemically discovered APA events with tissue-specific patterns and how age-associated APA changes in different tissues are attenuated by those pro-longevity mechanisms. APA plays a crucial role in the control of mRNA metabolism, gene regulation and protein diversification 51. Our study provides, to our knowledge, the first systematic profiling of APA changes at the whole transcriptome level. Interestingly, APA events exhibit tissue-specific distribution, undergo significant changes during aging and can be differentially regulated by different pro-longevity mechanisms. We discovered that, during aging, all cell types shift their APA preference toward the distal site, and this shifted preference is suppressed in the long-lived strains. Previous studies revealed that the usage of the distal APA site is inversely correlated with the level of core polyadenylation factors. Additionally, the increased usage of distal APA sites may lead to longer 3′ UTRs, which are associated with mRNA instability. Based on our findings, we speculate that, with aging, the level of core polyadenylation factors may decrease and the length of 3′ UTRs may increase, potentially resulting in declines in translational efficiency. Thus, suppressing the distal APA usage in the long-lived strains may help improve protein outputs, contributing to their longevity effects.

Adoptive cell therapies involve introducing immune cells to attack a specific issue in the body, most often cancer. The earliest forms of adoptive cell therapy used immune cells from another individual, but more modern approaches use a patient's own cells, expanded in culture and potentially engineered in various ways. Think of chimeric antigen receptor T cell (CAR-T) therapies, for example. Both T cells and natural killer (NK) cells have been employed as a basis for adoptive cell therapies targeted at cancer. In today's open access paper, researchers consider another potential use for adoptive NK cell therapy, as a way to produce lasting clearance of senescent cells in aged tissues. It is clear that NK cells, along with several other immune cell types, are involved in the normal processes of destruction of senescent cells as they show up in the body. Unfortunately, this immune mediated clearance of senescent cells slows down with advancing age, allowing the build up of lingering senescent cells throughout the body. Senescent cells produce signaling that is useful under various circumstances, such as suppression of potentially cancerous damage and coordination in wound healing, but when sustained for the long term becomes highly disruptive to tissue structure and function. Researchers have already demonstrated that CAR-T therapies can be adapted to target senescent cells. It is plausible that NK cell therapies can also serve this purpose. The question is whether the cost is worth it, when other forms of seno lytic therapy that are capable of training the immune system to more aggressively attack senescent cells, including the Deciduous Therapeutics approach, are far cheaper. The primary issue with adoptive cell therapies at the present time is their high cost, an unavoidable outcome of any therapy that requires weeks or months of effort to grow, engineer, and quality control large numbers of cells from a patient sample. That doesn't compete well with the need to treat every older individual on some intermittent, recurring basis. Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics As the global population ages, the prevalence of associated diseases becomes increasingly apparent. The pursuit of healthy aging, characterized by heightened resistance to lethal diseases, is the cornerstone of preventive medicine. The aging process is a complex process involving cellular senescence and inflammation, with the immune system playing a pivotal role in managing these aspects. Timely clearance of senescent cells (SNCs) is central to maintaining tissue and organismal homeostasis. Unfortunately, immunosenescence, a progressively dysregulated immune state with age, fails to eliminate SNCs, leading to their accumulation. This often coincides with the release of senescence-associated secretory phenotypes (SASPs), inhibiting immunity and increasing vulnerability to aging-associated diseases (AADs). Consequently, targeting immunosenescence and SNCs emerges as a crucial therapeutic strategy to preserve and extend healthy aging. While adaptive immunity has traditionally taken center stage in immunogerontological studies, growing evidence underscores the substantial impact of innate immunity in AADs. Natural killer (NK) cells, integral to the innate immune system, uniquely identify and eliminate aberrant cells such as tumor cells and virus-infected cells. Moreover, NK cells promptly address SNCs, and coordinate with other immune components through cytokine and chemokine production to surveil and eliminate cancer cells. Although whether the same occurs against SNCs remains to be determined. Evidence from healthy elderly individuals, especially those exhibiting physical fitness, independence in daily activities, or adequate cognitive function, the number and function of NK cells are highly preserved. Conversely, diminished NK cell activity in elderly individuals is associated with disorders such as atherosclerosis and an elevated risk of mortality. Accordingly, preserving NK cell function during aging is deemed crucial for healthy aging and longevity. Alternatively, NK-cell-based therapies, notably adoptive NK cell therapy, aligning with their established role in cancer and viral infection treatments, show promise in rejuvenating immunosenescence, eliminating SNCs and alleviating SASPs, that lead to AADs.

Whether it’s an old injury that keeps flaring up or the start of arthritis, you’re more likely to feel a few aches more often as you age. Regular movement can ease pain and make your joints more flexible. Try low-impact exercises like swimming, yoga, and tai-chi. Heating pads or ice packs can help, too. If those don’t give you enough relief, talk to your doctor about over-the-counter or prescription medicines, like nonsteroidal anti-inflammatory drugs (NSAIDs).

These show up as your skin gets thinner, drier, and less elastic. But some things can make them worse, like smoking and ultraviolet rays from the sun or a tanning bed. To ease these signs of aging, protect your skin from the sun, and if you smoke, quit. Some skin products, like moisturizers or prescription retinoids, might make wrinkles less noticeable. But you’ll need to give them time to work -- most need 6 weeks to 3 months to show results. A dermatologist can help you know what would work best for you.

Sun protection and quitting smoking will help this problem, too. So will watching how much alcohol you drink -- it can dehydrate you. It’s a good idea to keep showers or baths to less than 10 minutes and to use warm water instead of hot. Then put a heavy, oil-based moisturizer all over your body right away.

Many people lose strength and endurance as they get older, but the reason isn’t really about the aging process. Many people just stop working key muscles. The phrase “use it or lose it” applies here, so see if you can start weight training to build up your strength. Regular exercise, like walking, gardening, or swimming, can help, too. Aim for at least 30 minutes a day -- you can split it into two 15-minute sessions if that works better for you.

Your need for shut-eye doesn’t change as you age, but your ability to get it can. Older people tend to have a harder time falling asleep, have shorter stretches of deep sleep, and wake up more often in the middle of the night. Coffee and alcohol can cause those issues, so cutting back on those can help. And it’s important to keep health conditions that can affect your sleep, like high blood pressure or GERD, under control. Talk with your doctor if you often have trouble sleeping.

They might feel alarming, but they’re part of the normal aging process. Your brain changes as you get older, which can affect how well you remember things. You may need to lean on a few tricks, like keeping lists, following a routine, and putting items in a set place. But some habits also help you keep your memory sharp. For example, being around friends and family often has been shown to boost your brain power. Regular exercise and eating healthy foods are key, too.

As you get older, you don’t burn calories like you used to. But you can counter that slower metabolism by being more active and watching what and how much you eat. Make fruits, vegetables, and leaner protein key parts of your diet. Also, limit sugar and foods that are high in saturated fat. And keep an eye on portion sizes.

Erectile dysfunction, vaginal dryness, and other conditions that become more likely with age can make sex a challenge. Talk with your partner about how you’re feeling and if you

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