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  • Reviewing the Role of the Immune System in Clearance of Senescent Cells
  • Cyclic Peptides to Remodel the Gut Microbiome by Suppressing Growth of Harmful Bacteria
  • Nanoparticles Containing Cyclodextrins to Sequester Cholesterol Do Well in an Atherosclerosis Animal Model
  • A Study of Environmental Factors Correlating with the Odds of Becoming a Centenarian
  • Senescence-Associated Secretory Phenotype Proteins as a Biomarker of Aging
  • Towards the Use of Epigenetic Clocks in Clinical Trials
  • A Central Role for p53 in Osteoporosis?
  • The Immune Response to Tumors Changes with Age
  • The Challenge of Cellular Senescence in Mesenchymal Stem Cell Therapy
  • Lower Socioeconomic Status Correlates with Faster Age-Related Decline
  • Using the Metabolome to Produce an Aging Clock
  • Sedentary Behavior Raises the Risk of Cancer Mortality
  • Demonstrating a Senolytic Chimeric Antigen Receptor T Cell Therapy
  • Germline Mutation Rate as an Insight into the Pace of Aging
  • T Cells Must Work Harder to Survive in an Old Body

Reviewing the Role of the Immune System in Clearance of Senescent Cells

Cells in the body become senescent constantly, in response to reaching the Hayflick limit on replication, to DNA damage, to a toxic local environment, to injury. A senescent cell grows large, ceases replication, and secretes a potent mix of signals, the senescence-associated secretory phenotype (SASP). The SASP rouses the immune system into an inflammatory state, disrupts tissue maintenance and structure, and encourages other cells to also become senescent. In the short term this is a necessary part of wound healing and cancer suppression. If maintained for the long term, the SASP becomes very harmful, however.

Near all senescent cells cells are rapidly destroyed, either by programmed cell death or by the immune system. This is a requirement to maintain functional tissues, given the harms produced by a sustained SASP. Unfortunately senescent cells accumulate with age. It remains unclear as to the degree to which this is an imbalance between creation and destruction versus a small fraction of senescent cells being resistant to clearance. It is certainly the case that clearance mechanisms appear to slow down in older individuals, while on the other hand some senescent cells find ways to evade the immune system.

In today’s open access paper, researchers outline what is known of the role of the immune system in the clearance of senescent cells. It is likely that the characteristic age-related decline in immune function that takes place with advancing age is the most important determinant of the significant growth in the senescent cell burden in tissues in later life. This is one the many ways in which immune aging sabotages health and reduces life span.

Role of immune cells in the removal of deleterious senescent cells

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The SASP is conserved between mice and humans, and even to some extent between mammals and insects. Its components include growth factors, chemokines and cytokines, proteases, bioactive lipids and extracellular vesicles, many of which are pro-inflammatory. The number of senescent cells increases with age in most tissues, although they rarely exceed a few percent. Nonetheless, mounting evidence suggests that senescent cells can drive a surprisingly diverse array of aging phenotypes and diseases, mainly through the SASP. The presence of senescent cells also exacerbates several diseases including, but not limited to, osteoarthritis, osteoporosis, atherosclerosis, Parkinson’s disease, and Alzheimer’s disease.

Importantly, eliminating senescent cells in transgenic mouse models often delays age-related tissue dysfunction and increases health span. Furthermore, several laboratories are developing new classes of drugs termed senolytics, which kill senescent cells, or senomorphics, which alleviate SASP effects. These drugs can help maintain homeostasis in aged or damaged tissues, and postpone or ameliorate many age-related pathologies.

Current thinking is that the short-term presence of senescent cells is beneficial, largely by adjusting the plasticity of neighboring cells, but that their prolonged presence can be deleterious. The timely clearance of senescent cells is required to maintain tissue and organismal homeostasis. Although cellular senescence has been studied in detail in the context of disease, the interaction of senescent cells with immune cells have been less thoroughly investigated. Due in large measure to the SASP, senescent cells likely interact extensively with the immune system. The production and secretion of SASP factors (resulting in local inflammation) can be a potent means to recruit immune cells. The SASP recruits macrophages, natural killer (NK) cells, neutrophils, and T lymphocytes, which eliminate them, but senescent cells can also interact with immune cells to avoid elimination.

There are currently several immune cell therapies for cancer under development or approved, which could potentially be redesigned to target senescent cells. Chimeric antigen receptor (CAR) T cell therapy has been successful in recent years for treating diseases such as cancer. CAR-T cell therapy uses autologous cells that are genetically modified ex vivo to encode a synthetic receptor that binds a known antigen. The modified cells are then infused back into the patient to kill the target cells. Evidence that there are senescent-specific surface markers is spotty, and specificity needs further validation. Nonetheless, once a good target has been identified, it can be used to create a CAR-T cell.

As senescent cells are naturally targeted for elimination by NK cells, it could be beneficial to use NK cells to eliminate persistent pro-inflammatory senescent cells, particularly as they accumulate during aging. Even though technical, logistical, and financial challenges are still limiting factors for applications of circulating NK cells as promising cancer therapies, over the past decade, several studies demonstrated the safety and efficacy of allogeneic NK cells against various hematological malignancies. The same technology could be used to target senescent cells by NK cells.

Macrophages can eliminate senescent cells. Transplanted macrophages can migrate into tissues and become tissue-resident with much longer half-lives and self-renewal abilities. Because macrophages are phenotypically plastic, and cancer cells often express a “don’t eat me” signal, macrophage cell therapies have not been very successful in treating cancer. Whether this limitation poses a difficulty in using macrophages against senescent cells is not clear. NFκB-dependent pro-inflammatory signaling appears to upregulate the “don’t eat me” marker CD47, at least in some cancers, facilitating their escape from immune surveillance. Senescent cells generally upregulate NFκB activity, which can activate CD47 transcription.

A better understanding of the interplay between immune cells and senescent cells would illuminate changes that happen during aging, and also speed the development of novel therapeutic interventions for eliminating deleterious senescent cells. Different approaches could be formulated to remove senescent cells using the natural ability of immune cells. What is needed now is a more thorough understanding of the heterogeneity of senescent cells and of the specific targets for immune cells.

Cyclic Peptides to Remodel the Gut Microbiome by Suppressing Growth of Harmful Bacteria

Research into the effects of the gut microbiome on health and aging is presently flourishing. Scientists are identifying meaningful changes in microbial populations that take place with age, as well as metabolites generated by gut microbes that favorably influence health, such as indoles, butyrate, propionate, and so forth. With advancing age, the balance of microbial populations shifts from beneficial to harmful. The production of beneficial metabolites decreases. Microbes invade gut tissue to produce a state of chronic inflammation that spreads to accelerate the onset and progression of age-related disease throughout the body. The size of the contribution of the gut microbiome to the progression of aging is up for debate, but based on evidence from animal models it isn’t unreasonable to guess at it being in the same ballpark as the effects of exercise.

There are many possible causes of the age-related deterioration of the gut microbiome. Dietary changes, lesser degrees of exercise, dysfunction in intestinal tissues, the decline of immune function. The immune system plays a role in gardening the microbes of the gut, as illustrated by the fact that beneficial changes in the gut microbe can be produced via forms of immunization against bacterial proteins.

Regardless of cause, a range of strategies might be employed to readjust a dysfunctional gut microbiome to produce a better outcome for the individual. For example, fecal microbiata transplantation from young to old has been shown to extend life in short lived killifish. In principle similar effects could be achieved with aggressive use of probiotics, or methods of selective destruction of harmful microbes. The approach noted in today’s research materials is an example of the latter approach. Researchers have identified molecules that are harmless to cells, but suppress growth in some species of harmful gut microbes. The result is improved health in an animal model of a poor diet.

Molecules that reduce ‘bad’ gut bacteria reverse narrowing of arteries in animal study

The gut microbiome, which includes hundreds of bacterial species, evolved long ago as part of a fundamental symbiosis: The bacteria get a place to live and plenty to eat, and in return they assist their animal hosts, largely by helping them digest food. Scientists have learned that this symbiosis can have a downside for the bacteria’s human hosts. When people overuse antibiotics or consume “Western” diets rich in carbs, fats and sugar, the gut microbiome can be altered in ways that promote disease. Indeed, it now appears that the increased risks of obesity, diabetes, hypertension, and atherosclerosis that are conferred by the Western diet are due in part to adverse changes in the microbiome.

That recognition has led researchers to look for ways to remodel the microbiome. “Our approach, using small molecules called cyclic peptides, is inspired by nature. Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations.” the team already had a small collection of cyclic peptides that had been made using chemistry techniques. For the study, they set up a screening system to determine if any of those peptides could beneficially remodel the mammalian gut microbiome by suppressing undesirable gut bacterial species.

Using mice that are genetically susceptible to high cholesterol, they fed the animals a Western-type diet that swiftly and reliably produces high blood cholesterol and atherosclerosis, as well as adverse shifts in the gut microbiome. The researchers then sampled the animals’ gut contents and applied a different cyclic peptide to each sample. A day later, they sequenced the bacterial DNA in the samples to determine which peptides had shifted the gut microbiome in the desired direction.

The scientists soon identified two peptides that had significantly slowed the growth of undesirable gut bacteria, shifting the species balance closer to what is seen in mice that are fed a healthier diet. Using these peptides to treat atherosclerosis-prone mice that were eating a high-fat Western diet, they found striking reductions in the animals’ blood levels of cholesterol compared to untreated mice – about 36 percent after two weeks of treatment. They also found that after 10 weeks, the atherosclerotic plaques in the arteries of the treated mice were about 40 percent reduced in area, compared to those in untreated mice.

Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis

The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state.

Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α, and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

Nanoparticles Containing Cyclodextrins to Sequester Cholesterol Do Well in an Atherosclerosis Animal Model

Cyclodextrins bind to cholesterol. This aspect of their biochemistry has been used by the Underdog Pharmaceuticals team to produce a cyclodextrin that binds the form of toxic oxidized cholesterol known as 7-ketocholesterol. 7-ketocholesterol builds up with age and is implicated in a range of age-related conditions, particularly atherosclerosis, as altered cholesterols cause dysfunction in the macrophage cells responsible for removing cholesterols and other lipids from blood vessel walls. The outcome is the creation of fatty lesions that narrow and weaken blood vessels in older individuals, an ultimately fatal condition. Removing 7-ketocholesterol and other problem altered cholesterols is a promising approach to therapy.

In today’s research materials, the authors report on a different way to use an existing cyclodextrin to tackle atherosclerosis. They encapsulate molecules of the cyclodextrin and a statin in nanoparticles. The nanoparticles release the statin in atherosclerotic lesions, and take in cholesterol molecules that bind to the cyclodextrin. This sequestering of cholesterol aids macrophages in their work, most likely through binding some fraction of the altered cholesterols that cause issues, and results in a sizable reduction in the lesion size in a mouse model. Around a 50% reversal of atherosclerotic lesions is about the best that has been achieved in mice, and this is in that ballpark, averaged over different portions of the aorta. We might take this as helpful support for the Underdog Pharmaceuticals approach.

New nanoparticle drug combination for atherosclerosis

Physicochemical cargo-switching nanoparticles (CSNP) can help significantly reduce cholesterol and macrophage foam cells in arteries, which are the two main triggers for atherosclerotic plaque and inflammation. The CSNP-based combination drug delivery therapy was proved to exert cholesterol-lowering, anti-inflammatory, and anti-proliferative functions of cyclodextrin and statin, two common medications for treating and preventing atherosclerosis.

Researchers reported that the polymeric formulation of cyclodextrin with a diameter of approximately 100 nm can accumulate within the atherosclerotic plaque and effectively reduce the plaque even at lower doses, compared to cyclodextrin in a non-polymer structure. Moreover, although cyclodextrin is known to have a cytotoxic effect on hair cells in the cochlea, which can lead to hearing loss, cyclodextrin polymers developed by the research group exhibited a varying biodistribution profile and did not have this side effect.

The researchers exploited the fact that cyclodextrin and statin form the cyclodextrin-statin self-assembly drug complex, based on previous findings that each drug can exert local anti-atherosclerosis effect within the plaque. The complex formation processes were optimized to obtain homogeneous and stable nanoparticles with a diameter of about 100 nm for systematic injection. The therapeutic synergy of cyclodextrin and statin could reportedly enhance plaque-targeted drug delivery and anti-inflammation. Cyclodextrin led to the regression of cholesterol in the established plaque, and the statins were shown to inhibit the proliferation of macrophage foam cells.

Affinity-Driven Design of Cargo-Switching Nanoparticles to Leverage a Cholesterol-Rich Microenvironment for Atherosclerosis Therapy

Atherosclerotic plaques exhibit high deposition of cholesterol and macrophages. These are not only the main components of the plaques but also key inflammation-triggering sources. However, no existing therapeutics can achieve effective removal of both components within the plaques. Here, we report cargo-switching nanoparticles (CSNP) that are physicochemically designed to bind to cholesterol and release anti-inflammatory drug in the plaque microenvironment. CSNP have a core-shell structure with a core composed of an inclusion complex of methyl-β-cyclodextrin (cyclodextrin) and simvastatin (statin), and a shell of phospholipids.

Upon interaction with cholesterol, which has higher affinity to cyclodextrin than statin, CSNP release statin and scavenge cholesterol instead through cargo-switching. CSNP exhibit cholesterol-sensitive multifaceted anti-atherogenic functions attributed to statin release and cholesterol depletion in vitro. In mouse models of atherosclerosis, systemically injected CSNP target atherosclerotic plaques and reduce plaque content of cholesterol and macrophages, which synergistically leads to effective prevention of atherogenesis and regression of established plaques. These findings suggest that CSNP provide a therapeutic platform for interfacing with cholesterol-associated inflammatory diseases such as atherosclerosis.

A Study of Environmental Factors Correlating with the Odds of Becoming a Centenarian

The evidence to date strongly suggests that environmental factors determine longevity for the vast majority of people. If there are significant longevity-affecting gene variants out there, then they have small and unreliable effects (APOE), or are restricted to tiny lineages (SERPINE1), or both. The overwhelming majority of contributions to longevity emerge from lifestyle choices relating to weight, exercise, smoking, and so forth, and exposure to persistent pathogens such as cytomegalovirus. In the near future we’ll add access to rejuvenation therapies to this list, but that is only just getting underway now and isn’t yet relevant to epidemiological studies of older people.

Today’s open access paper on environment and lifestyle choice versus the odds of becoming a centenarian is interesting for showing a few correlations that stand in opposition to the rest of the literature. For example, lower educational achievement and being widowed correlates with greater odds of living to 100 in this study. This is perhaps a good example of the perils of epidemiology, and particularly the challenges inherent in reasoning about epidemiological data. One should never take any one paper at face value without considering the rest of the literature, and one should bear in mind that different views (just people in one geographic area) or slices of data (just older people) may well produce opposing results.

Environmental Correlates of Reaching a Centenarian Age: Analysis of 144,665 Deaths in Washington State for 2011-2015

The survival probability of becoming a centenarian has been shown to be multifactorial. The rapid increase in the odds of living to 100 years of age is largely due to substantial advancements in medicine and public health that decreased the burden of disease. Genetic factors, including genes in several pathways influencing longevity, such as inflammation and immunity, have also been explored. These studies have shown that longevity is likely to be a polygenic trait, but aging has been attributed to be only 20-35% heritable. Social and environmental factors, such as high educational attainment and socioeconomic status, also significantly contribute to longevity.

This study aimed to examine the likelihood of becoming a centenarian for adults aged 75 and above in Washington State and to identify social and environmental correlates of healthy aging and longevity. In addition, we identified geographic clusters within Washington State where individuals are more likely to become centenarians. Models were adjusted for sex, race, education, marital status, and neighborhood level social and environmental variables at the block group level. In the adjusted model, increased neighborhood walkability, lower education level, higher socioeconomic status, and a higher percent of working age population were positively associated with reaching centenarian age. Being widowed, divorced/separated, or never married were also positively correlated compared to being married. Additionally, being white or female were positively correlated with reaching centenarian status.

Surprisingly, education was found to be negatively associated with becoming a centenarian. In recent studies, higher education levels have been strongly associated with lower mortality. Higher academic level indicates employment opportunities and lifestyles associated with factors such as socioeconomic status, social connections, availability and knowledge of health resources, health behaviors (e.g., not smoking), and critical thinking skills applied to managing health problems.

Rapid advances in educational attainment in the last few generations may explain, in part, the lack of a positive association between educational attainment and becoming a centenarian in our study. In this regard, in 1950, only 34.3% of the U.S. population above the age of 25 had a high school diploma, a figure that increased to more than 80% by 2000. More recent studies have demonstrated increasing declines in mortality with education, suggesting that education is less of a factor in determining longevity in older populations.

Another unexpected finding was that compared to married older adults, those who never married, or were widowed, or divorced/separated were more likely to become centenarians. Being widowed showed the greatest benefit, with never having married coming second, and being divorced/separated showing the least benefit. Decades of work have consistently observed that marriage is associated with longer survival than being divorced or never having married. However, this study specifically focused on those aged 75 and above, so the selection aspect and some of the protective factors may not be as relevant.

Many studies have not explored the effects of marital status on health at older ages specifically. In this study, the finding of a much greater likelihood of becoming a centenarian for those who are widowed may be partially explained by the fact that those who lost their spouses earlier in life may no longer experience the stresses associated with the traumatic event. This line of reasoning may also contribute to the findings around being divorced/separated leading to a greater likelihood of becoming a centenarian, which is not generally consistent with prior research.

Senescence-Associated Secretory Phenotype Proteins as a Biomarker of Aging

In today’s open access research, the authors report on the generation of a biomarker of aging from the study of proteins secreted by senescent cells. Low cost assays that map closely to biological age, the burden of damage, are a potentially useful tool for research and development of rejuvenation therapies. This biomarker is likely not general enough for that role; the accumulation of senescent cells with age in tissues throughout the body is just one of a number of mechanisms important in degenerative aging. It is always good to have further evidence that senescent cells are important in aging, to add to the very compelling animal studies that demonstrate rejuvenation when senescent cells are selectively destroyed, but an assay that reflects senescent cell burden is probably not helpful in the assessment of a candidate rejuvenation therapy that targets other mechanisms of aging.

Cells become senescent constantly, at all ages, largely somatic cells hitting the Hayflick limit on cellular replication. Cells also enter senescence when damaged, or in response to a toxic environment, or to aid in wound healing. That damaged cells become senescent helps to suppress cancer risk. This is all beneficial, so long as the senescent cells are promptly destroyed. A senescent cell releases into the surrounding environment a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). The SASP rouses the immune system to inflammation, remodels tissue structure, and changes cell behavior, among other effects. This is beneficial in the short term, but becomes very damaging when sustained for the long-term. The lasting inflammation and disruption of tissue structure caused by senescent cells lingering in old tissues contributes meaningfully to the onset and progression of many age-related diseases.

The senescence-associated secretome as an indicator of age and medical risk

Aging is the strongest risk factor for the majority of chronic diseases. Recent scientific advances have led to the transformative hypothesis that interventions targeting the fundamental biology of aging have the potential to delay, if not prevent, the onset of age-associated conditions and extend human health span. Notably, there is now compelling evidence that cellular senescence, a state of stable growth arrest caused by diverse forms of cellular and molecular damage, contributes to aging, in part, through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate with advancing age. Preclinical studies in rodents have established that transgenic strategies and drugs that selectively kill senescent cells improve numerous yet pathologically distinct conditions of aging.

Dramatic variability is inherent to aging. Many older adults of a given chronological age experience multiple chronic conditions and functional limitations, while paired-age counterparts may have low or no disease burden and comparatively greater functional independence. Advanced biological age may be linked to a greater burden of senescent cells in one or multiple organs. Core properties of senescent cells include upregulation of cyclin-dependent kinase inhibitors, morphological changes, activation of anti-apoptosis pathways, and a SASP composed of cytokines, chemokines, matrix remodeling proteins, and growth factors.

Senescent cell properties can be quantified in isolated tissues; however, this poses practical challenges for human application. Since the SASP is a key pathogenic feature of senescent cells, leveraging the circulating SASP as an indicator of systemic senescent cell burden may offer considerable utility. In clinical research, it can help identify persons who may be most responsive to emerging therapies and serve as surrogate endpoints in associated clinical trials. In clinical practice, SASP quantification may identify persons of advanced biological age and guide clinical decision making. We hypothesize that SASP abundance may be associated with chronological aging and accelerated biological aging.

We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis or ovarian cancer were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes.

We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

Towards the Use of Epigenetic Clocks in Clinical Trials

Despite the challenges inherent in the practical use of epigenetic clocks based on age-related changes in DNA methylation, clinical trials are forging ahead in the employment of these clocks. The assays are cheap enough that there is a sense of “why not?” and, considered over patient populations rather than in individuals, an epigenetic age higher than chronological age correlates well with risk and progression of age-related disease. It remains problematic for any given individual to extract meaning from an epigenetic clock assay, however. It is unclear as to what exactly the measured age-related changes in DNA methylation reflect, in terms of the underlying damage and dysfunction of aging, and thus results are not yet actionable for the individual.

Geroscience is a developing discipline based on the premise that health can be improved by targeting aging. Clinical trials are underway to test the geroscience hypothesis in humans. Definitive tests of the hypothesis must demonstrate reduced rates of age-related diseases and death, but the length of time and size of trial needed to test the hypothesis are both substantial. Therefore, objective, quantifiable characteristics of the aging process – known as biomarkers – that can be tracked in clinical trials are needed for the field to progress.

Useful biomarkers should meet several criteria: i) their measurement should be reliable and feasible; ii) they should be relevant to aging; iii) they should robustly and consistently predict trial endpoints, such as functional ability, disease, or death; and iv) they should be responsive to interventions such as treatments targeting aging biology. Practically speaking, this means that a change in the level of a biomarker should parallel changes in the susceptibility to disease, age of death, or loss of function. Interventions that target aging and support the geroscience hypothesis should therefore also lead to changes in these biomarkers, which will be reflected in the incidence or severity of age-related diseases and functional decline.

Biomarkers based on DNA methylation levels look promising. Briefly, these biomarkers quantify the proportion of cells in which a gene locus is methylated. Small but consistent changes in the methylation of some loci occur in organisms with older ages, and early methods for estimating age using epigenetics took advantage of these chronologic changes. However, critics argue that while these ‘clocks’ may be associated with chronological age, it is uncertain whether they reflect meaningful change in the context of interventions affecting the underlying biology.

Estimators based on the levels of DNA methylation are now being developed to detect a myriad of disease states and predict mortality and adverse health events, and each is unique to its calibration method. Now researchers report the development of a new epigenetic biomarker called Dunedin Pace of Aging methylation (DunedinPoAm) that is able to detect how aging phenotypes change over time. The new biomarker relies on a composite measure called the Pace of Aging. Pace of Aging is calculated based on a number of age-related phenotypic changes that occur over time. In the new work this measure was used to calibrate and validate a DNA-wide methylation clock in four independent cohorts.

Is DunedinPoAm developed to the point where it could be relied upon as a biomarker for clinical trials targeting biological aging? DunedinPoAm appears to satisfy the criteria aside from being responsive to interventions. One of the cohorts used to validate the new approach consisted of middle-aged, non-obese adults enrolled in the CALERIE trial. This trial tested the effects of caloric restriction – an intervention that has been successful in animal models – over a period of two years. DunedinPoAm was able to predict changes in the Pace of Aging measure in the control group, but not in the group that had been calorie restricted. However, it remains to be seen whether interventions which affect aging biology change DunedinPoAm in a way that is consistent with the phenotypic changes observed in the trial. Testing the geroscience hypothesis in clinical trials is still in its early days, so it is not surprising that DunedinPoAm does not yet meet the primary criterion for an aging biomarker.

A Central Role for p53 in Osteoporosis?

Osteoporosis is the name given to the advanced stages of the characteristic age-related loss of bone strength and density. Bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. With advancing age, the activity of osteoclasts begins to dominate, and thus bone becomes ever weaker and lighter, with eventually disastrous consequences. There are many possible contributing causes for this imbalance between cell types, most of which are present in all older individuals. It is therefore interesting to speculate on why only some people progress to clinical osteoporosis. Hence studies of the sort noted here, in which researchers attempt to pick apart the complexities of the disease state, in search of noteworthy differences between older individuals with and without clinical osteoporosis.

Osteoporosis is a metabolic disease characterized by decreased bone mass per unit volume, despite the bone tissue having normal calcification and a normal ratio of calcium salt and matrix. As one of the most commonly occurring chronic diseases among the elderly, osteoporosis has become a serious problem for public health care systems. The pathogenesis of osteoporosis has not yet been fully elucidated. Factors that inhibit osteogenesis, promote bone resorption, or cause bone microstructural destruction may play a role in the development of osteoporosis, and a variety of genes may be directly or indirectly involved.

In the present study, we applied bioinformatic analysis of an osteoporosis microarray dataset retrieved from the Gene Expression Omnibus (GEO) to explore the mechanisms underlying osteoporosis. We analyzed the interactions among involved proteins and ranking the top 10 hub genes. The identified hub genes were TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2, and CYCS. Moreover, we found that nearly all of the top 10 hub genes were involved in the top five enriched Gene Ontology terms or KEGG pathways, indicating their potential roles in osteoporosis progression. Consistent with our findings, a number of studies have previously reported the involvement of TP53, MAPK1, CASP3, CTNNB1, CCND1, NOTCH1, CDK1, IGF1, ERBB2 in osteoporosis or osteogenesis.

P53 had the highest degree score in the network, indicating it may play a central role during the development of osteoporosis. P53 is encoded by the tumor suppressor gene TP53 and suppresses tumor growth by slowing cell growth and division. In the present study, it is found that serum p53 levels are increased in osteoporosis patients, and knocking down p53 partially reversed decreases in bone mineral density in vitro and in vivo. In addition, GO and KEGG enrichment analyses indicate that p53 is involved in “the cancer pathway,” “proteoglycans in cancer pathway,” and “P53 signaling pathway.” We therefore suggest that p53 may contribute to the pathogenesis of osteoporosis via these pathways.

The Immune Response to Tumors Changes with Age

The interaction between the immune system and tumor is meaningfully different in young and old individuals. The aging of the immune system makes near everything worse in health and physiology. It greatly affects risk of cancer, in the sense of determining whether pre-cancerous cells are eliminated before they can gain a foothold. It also affects the distribution of cancer types, for reasons that are not fully explored. Further, and as discussed here, it affects the efforts of the immune system to destroy an established tumor.

Advanced age is strongly correlated with both increased cancer incidence and general immune decline. The immune tumor microenvironment (ITME) has been established as an important prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune decline is an important consideration for the treatment of a large subset of cancer patients. Current studies of aging-related immune alterations are predominantly performed on non-cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration.

We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the Genotype-Tissue Expression project to distinguish normal age-related immune alterations from age-related changes in tumor immune infiltration. We demonstrate that while there is overlap between the normal immune aging phenotype and that of the ITME, there are several changes in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and macrophage populations.

These results suggest that aged immune cells are more susceptible to tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which creates an unfavorable ITME in older patients in excess of normal immune decline with age and may inform the application of existing and emerging immunotherapies for this large population of patients. We additionally identify that age-related increases in tumor mutational burden are associated with decreased DNA methylation and increased expression of the immune checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic application of immune checkpoint blockade in older patients.

The Challenge of Cellular Senescence in Mesenchymal Stem Cell Therapy

The accumulation of senescent cells in tissues throughout the body is a cause of aging, but it is also a phenomenon that occurs in cell cultures. Senescent cells do not replicate and secrete a potent inflammatory mix of signal molecules that degrades tissue function. Senescence in cells expanded in culture is a challenge to the efficacy of cell therapies, and may go some way towards explaining the unreliability in benefits obtained from clinic to clinic and treatment to treatment. First generation mesenchymal stem cell therapies are now widely employed, and researchers are starting to give greater attention to ways to minimize senescence in the cells delivered to patients.

Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation. There is increasing evidence of the therapeutic value of MSCs in various clinical situations, however, these cells gradually lose their regenerative potential with age, with a concomitant increase in cellular dysfunction. Stem cell aging and replicative exhaustion are considered as hallmarks of aging and functional attrition in organisms. MSCs do not proliferate infinitely but undergo only a limited number of population doublings before becoming senescent. This greatly hinders their clinical application, given that cultures must be expanded to obtain a sufficient number of cells for cell-based therapy.

Strategies allowing the generation of large numbers of MSCs that have retained their stemness are needed for clinical applications. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) can be passaged more than 40 times without exhibiting features of senescence. iMSCs retain a donor-specific DNA methylation profile while tissue-specific, senescence-associated, and age-related patterns are erased during reprogramming. Recent studies have demonstrated that iMSCs have superior regenerative capacity compared to tissue-derived MSCs in preclinical degenerative disease models. However, the generation of iMSCs from iPSCs requires a significant degree of molecular manipulation, and there are safety concerns regarding the self-renewal and pluripotency of iPSC-derived cells after in vivo transplantation.

Aging is not a passive or random process but can be modulated through several key signaling molecules/pathways. Identification of age-related coordinating centers can provide novel targets for therapeutic interventions. Sirtuins (SIRTs) are a class of highly conserved nicotinamide adenine dinucleotide-dependent protein deacylases. The role of SIRTs in aging is related to their regulation of energy metabolism, cell death, and circadian rhythm and maintenance of cellular and mitochondrial protein homeostasis. Overexpression of SIRTs has been investigated as a potential strategy for preventing MSC aging. For instance, SIRT3 expression in MSCs decreased with prolonged culture and its overexpression in later-passage cells restored differentiation capacity and reduced aging-related senescence.

Genetic engineering has been used to slow MSC aging. Besides SIRTs, several molecules have been identified as potential targets for interventions to prevent senescence. Ectopic expression of telomerase reverse transcriptase in MSCs extended their replicative lifespan, which preserved a normal karyotype, promoted telomere elongation, and abolished senescence without loss of differentiation potential. Introduction of Erb-B2 receptor tyrosine kinase 4 (ERBB4) in aged MSCs conferred resistance to oxidative stress-induced cell death and rescued the senescence phenotype. Knocking down macrophage migration inhibitory factor (MIF) in young MSCs induced senescence; conversely, its overexpression in aged MSCs rejuvenated the cells by activating autophagy. However, the risk of malignant transformation remains a major barrier for the use of genetics-based approaches in clinical practice.

Lower Socioeconomic Status Correlates with Faster Age-Related Decline

There is a well-established web of correlations between life expectancy, wealth, intelligence, education, and social status. It is challenging to pick apart the underlying mechanisms, however, given demographic and epidemiological data as a starting point. For example, a slow debate is presently underway regarding the degree to which the correlation between intelligence and life expectancy has genetic origins, in that more physically robust people tend to be more intelligent, versus the more obvious suggestion that intelligent people tend to take better care of their health. That low socioeconomic status correlates with an accelerated onset of age-related declines in health also has the look of being explicable through worse maintenance of health over the long term: the usual triad of diet and weight, exercise, and smoking. That said, this study controlled for smoking, which makes it more interesting than the usual such work.

Lower socioeconomic status (SES) is a determinant of many of the health problems that emerge at older ages. The extent to which lower SES is associated with faster decline in age-related functions and phenotypes independently of health conditions is less clear. This study demonstrates that lower SES (defined by wealth) is related to accelerated decline over 6 to 8 years in 16 outcomes from physical, sensory, physiological, cognitive, emotional, and social domains, independently of diagnosed health conditions, self-rated health, education, and other factors. It provides evidence for the pervasive role of social circumstances on core aging processes and suggests that less affluent sectors of society age more rapidly than more privileged groups.

Aging involves decline in a range of functional abilities and phenotypes, many of which are also associated with socioeconomic status (SES). Here we assessed whether lower SES is a determinant of the rate of decline over 8 years in six domains – physical capability, sensory function, physiological function, cognitive performance, emotional well-being, and social function – in a sample of 5,018 men and women aged 64.44 (standard deviation 8.49) years on average at baseline. Wealth was used as the marker of SES, and all analyses controlled for age, gender, ethnicity, educational attainment, and long-term health conditions.

Lower SES was associated with greater adverse changes in physical capability (grip strength, gait speed, and physical activity), sensory function (sight impairment), physiological function (plasma fibrinogen concentration and lung function), cognitive performance (memory, executive function, and processing speed), emotional well-being (enjoyment of life and depressive symptoms), and social function (organizational membership, number of close friends, volunteering, and cultural engagement). Effects were maintained when controlling statistically for other factors such as smoking, marital/partnership status, and self-rated health and were also present when analyses were limited to participants aged ≤75 years of age. We conclude that lower SES is related to accelerated aging across a broad range of functional abilities and phenotypes independently of the presence of health conditions and that social circumstances impinge on multiple aspects of aging.

Using the Metabolome to Produce an Aging Clock

It has been a while now since the development of the first epigenetic clock, a weighted combination of DNA methylation sites that correlates tightly with chronological age. More interesting is that epigenetic ages higher than chronological ages correlate with age-related mortality, as well as risk and progression of numerous age-related diseases. This has inspired all sorts of similar efforts to produce clocks based on the wealth of data that can be assessed from blood, tissue, and other samples. Here, researchers discuss their work on a clock derived from the metabolome, the diverse collection of metabolites present in a biological sample. This research into biomarkers of aging is hoped to lead to a fast, cheap, and effective method to assess potential rejuvenation therapies: test shortly before and shortly after treatment, and compare. We’re not there yet, however.

Since aging is a process that affects almost all tissues and organs and involves crosstalk between multiple physiological systems, there has been increased research into composite markers of aging, involving multiple parameters. Biological age scores have been developed by combining established clinical biomarkers and have been associated with measures of functional decline such as cognitive ability.

Modern “omics” platforms have provided new opportunities for the systematic and agnostic assessment of biological aging. Analysis of genome-wide DNA methylation, mRNA, and miRNAs has allowed the development of multi-parameter “omic clocks,” built upon molecular changes that tick at an average rate consistent with chronological age. DNA methylation age acceleration, defined as having a greater DNA methylation age than chronological age (i.e., a faster than average “ticking rate”), is associated with multiple noncommunicable disease (NCD) risk factors and predictive of aging outcomes such as frailty, cognitive decline, and all-cause mortality.

Metabolomics, the profiling of small molecules, is a promising technology for the comprehensive assessment of biological aging. As the final product of cellular metabolism, metabolites may provide a more complete picture of biological processes and a stronger phenotypic representation than other “omic profiles.” Although metabolomic studies have reported strong associations between metabolites and age, these have been of limited sample size.

We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality.

The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use, and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension, and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.

Sedentary Behavior Raises the Risk of Cancer Mortality

Living a sedentary lifestyle is known to be harmful to long term health, raising the risk of age-related disease and mortality. Researchers here show that a sedentary life specifically increases cancer mortality, and does so independently of other factors. This is one of many, many reasons to maintain a regular schedule of exercise.

In the first study to look at objective measures of sedentary behavior and cancer mortality, researchers found that greater inactivity was independently associated with a higher risk of dying from cancer. The most sedentary individuals had an 82% higher risk of cancer mortality compared to the least sedentary individuals. Researchers also found that replacing 30 minutes of sedentary time with physical activity was associated with a 31% lower risk of cancer death for moderate-intensity activity, such as cycling, and an 8% lower risk of cancer death for light-intensity activity, such as walking.

This study involved a cohort of participants from the nationally representative REGARDS study, which recruited more than 30,000 U.S. adults over the age of 45 between 2003 and 2007 to study long-term health outcomes. To measure sedentary behavior, 8,002 REGARDS participants who did not have a cancer diagnosis at study enrollment wore an accelerometer on their hip during waking hours for seven consecutive days. The accelerometer data was gathered between 2009 and 2013. After a mean follow-up of 5 years, 268 participants died of cancer. Longer duration of sedentary behavior was independently associated with a greater risk of cancer death.

The study also found that engaging in either light or moderate to vigorous physical activity made a difference. Investigators assessed sedentary time, light-intensity physical activity (LIPA) and moderate to vigorous physical activity (MVPA) in the same model and found that LIPA and MVPA, not sedentary behavior, remained significantly associated with cancer mortality. “From a practical perspective, this means that individuals who replaced either 10 to 30 minutes of sedentary time with either LIPA or MVPA had a lower risk of cancer mortality in the REGARDS cohort.”

Demonstrating a Senolytic Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor (CAR) T cell therapies target specific surface features on other cells by providing T cells with a way to recognize that feature – the CAR. T cells so equipped will selectively destroy other cells with the target surface feature. To produce a CAR T cell therapy, a patient’s T cells are taken, genetically engineered to introduce the CAR, expanded, and then reintroduced. This is presently used as a form of cancer therapy. Given a surface feature sufficiently specific to senescent cells, CAR T cell immunotherapy can be turned into a senolytic treatment, however. Senescent cell accumulation is one of the important causes of degenerative aging, and effective clearance of senescent cells is a form of rejuvenation. Researchers here claim to have identified a suitably specific surface marker of senescence, and use it to demonstrate benefits in mice via CAR T cell therapy. It will be interesting to see how this develops.

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has a beneficial role in wound-healing responses. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity.

Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR) as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

Germline Mutation Rate as an Insight into the Pace of Aging

DNA sequencing over generations can be used to determine individual rates of germline mutation, as mutations present in the child but not the parent must have occurred in the parent germline. Stochastic nuclear DNA damage takes place over the course of aging, and evidence suggests that this correlates with the pace at which a person is aging. While nuclear DNA damage determines cancer risk, the degree to which it contributes to other forms of age-related degeneration is an open question. Only damage occurring in stem cells or progenitor cells, and that can thus spread through tissue in daughter somatic cells, seems likely to have a meaningful effect. Interventions such as calorie restriction, known to slow aging and extend life in laboratory species, do slow the onset of such unrepaired damage to nuclear DNA. All of this makes the research noted here quite interesting.

Scientists have long known that DNA damage constantly occurs in the body. Typically, various mechanisms repair this damage and prevent potentially harmful mutations. As we get older, these mechanisms become less efficient and more mutations accumulate. Older parents, for instance, tend to pass on more genetic mutations through their germline (egg and sperm) to their children than younger parents.

Researchers theorized that these mutations could be a biomarker for rates of aging and potentially predict lifespan in younger individuals as well as fertility in women. The researchers sequenced DNA from 61 men and 61 women who were grandparents in 41 three-generational families. The families were part of the Centre d’Etude du Polymorphisme Humain (CEPH) consortium, which was central to many key investigations that have contributed toward a modern understanding of human genetics.

The researchers analyzed blood DNA sequences in trios consisting of pairs of grandparents from the first generation and one of their children from the second generation. That’s because germline mutations are passed on to their offspring. Mutations found in the child’s blood DNA that were not present in either parent’s blood DNA were then inferred to have originated in the parents’ germlines. The researchers were then able to determine which parent each germline mutation came from, and, therefore, the number of such mutations each parent had accumulated in egg or sperm by the time of conception of the child.

Knowing that allowed the researchers to compare each first-generation parent to others of the same sex and estimate their rate of aging. “Compared to a 32-year-old man with 75 mutations, we would expect a 40-year-old with the same number of mutations to be aging more slowly. We’d expect him to die at an older age than the age at which the 32-year-old dies.” The scientists found that mutations began to occur at an accelerating rate during or soon after puberty, suggesting that aging begins in our teens. Some young adults acquired mutations at up to three times the rate of others. After adjusting for age, the researchers determined that individuals with the slowest rates of mutation accumulation were likely to live about five years longer than those who accumulated mutations more rapidly.

T Cells Must Work Harder to Survive in an Old Body

T cells of the adaptive immune system collectively become less functional with age. The immune system as a whole becomes more inflammatory and less effectively, a state described by the terms inflammaging and immunosenescence. Researchers here note that T cells struggle to survive in the aged environment, and are as a consequence metabolically inefficient. Their efforts are going towards survival rather than the activities of immune surveillance. The degree to which this contributes to immunosenesence versus other factors is an open question.

In a recent study, researchers outline that the increased metabolism of T cells observed with advanced age was an indication that they were working harder merely to survive. This contradicts previous knowledge, which suggested an increased metabolism was indicative of T cell function, and will have implications for the development of targeted interventions such as vaccines or immunotherapies to treat age-related immune dysfunction.

T cells play an important role in the body’s immune response to viral infections and tumors, but T cell immunity wanes as we age, thus increasing our susceptibility to these diseases. “We’ve shown that an amped-up metabolism, rather than arming cells to fight pathogens better, is associated with T cell survival over a lifespan. The cells need to substantially increase their metabolism just to survive in the relatively hostile environment of the elderly. This work is important because one of the hallmarks of immune aging is the loss of T cells. Ultimately we want to support healthy ageing by designing ways to improve T cell metabolism during cell-based immunotherapies such as CAR T cell therapy, and boosting T cell activation in new vaccines.