The geroscience hypothesis, that the rate of aging can be changed, is indeed an exciting one, and one that will likely receive considerable attention in the future. Geroprotectors arising from studies exploring the geroscience hypothesis would undoubtedly revolutionize health care and result in dramatic societal changes, and for these reasons should be taken extremely seriously. However, the biomedical science community should be very sensitive to overenthusiasm concerning ways in which geroprotectors are vetted, since reliance on a solitary measure of aging, for example an epigenetic clock, to vet candidate geroprotectors might not be necessary. If geroprotectors, by definition, should improve health during the aging process, and health can be measured in myriad ways, then relevant trials should focus on these health measures directly.

In fact, as we have argued, it would be hard to make the case that a geroprotector that is only known or shown to modulate an epigenetic clock will extend health span or lifespan without impacting anything associated with health from traditional clinical perspectives. In addition, if one could show that a geroprotector actually does modulate age-related disease processes using routine and accepted clinical measures then the mechanism of action of that geroprotector is likely to be a key to an underlying universal aging clock. Ultimately, a purported geroprotector that has either no observable effect on many available common sense, well-accepted measures of health and vitality, or will only have an effect on health via some cryptic mechanism after the many years of use during which an individual is at typical risk for disease, is a tough sell.

Simply put, geroprotectors should provide overt health and disease prevention benefits but the time-dependent relationships between epigenetic clocks and health-related phenomena are complex and in need of further scrutiny. Therefore, studies that enable understanding of the relationships between epigenetic clocks and disease processes while simultaneously testing the efficacy of a candidate geroprotector are crucial to move the field forward.

It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota-gut-brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer's disease (AD).

How the blood-brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation.

Gut microbiota-induced systemic chronic inflammation mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging.

Age is a prominent risk factor for most types of cancer. Cancer risk increases with age, in part, because genetic mutations that arise from DNA replication errors and exposure to environmental carcinogens accumulate as we get older. Aging also alters the epigenome, the chemical marks spread across DNA that help switch genes on or off by altering how the genome is packaged. For instance, the addition of a methyl group to DNA can play a role in compressing the nearby DNA sequence so it can no longer be accessed by the cell's machinery. Epigenetic modifications, including DNA methylation, have also been shown to contribute to the development of cancer. However, the potential impact of age-related epigenetic changes on cancer development has not been fully characterized.

It has been hypothesized that people whose epigenetic age is greater than their age in years - a phenomenon known as accelerated aging - may be at higher risk of age-related diseases, including cancer. However, previous studies linking accelerated epigenetic aging and cancer have produced mixed results. Now a team has taken a different approach. Instead of associating a person's risk of cancer with epigenetic clock estimates, they correlated it against genetic variations that are known to influence these algorithms.

The results did not show many clear relationships between the epigenetic aging clocks and risk for the various types of cancer studied. The most promising finding was an association between the GrimAge clock and colorectal cancer. The GrimAge clock was not designed to predict age alone, but also reflects the effects of smoking and other mortality-related epigenetic features. Thus, the interpretation of this association is not straightforward, as this clock may capture the effects of environmental or lifestyle factors on the epigenome. One caution is that epigenetic clocks have largely been developed based on how aging affects DNA methylation in blood cells. Much less is known regarding aging and epigenetics in other tissue types, including those prone to cancer.

Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina.

Using fecal microbiota transplantation (FMT), we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing.

We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota.

These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut-brain and gut-retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life.

Timing feedings to match the active period of the circadian cycle extended the life span of lab mice more than three times as much as caloric restriction alone. Mice that ate as much and whenever they wanted lived nearly 800 days median life span - an average period for their species. Restricting calories but making food available around the clock extended their lives only 10% to 875 days despite restricting calories by 30-40%. Restricting this reduced-calorie diet to the inactive period of the circadian cycle boosted lifespan by nearly 20% to an average of 959 days. Offering the low-calorie diet only during the active period of the cycle extended their median life span to about 1,068 days, an increase of almost 35% over the unrestricted eaters.

Further investigation showed that the mice that lived the longest had significantly better metabolic health, with higher insulin sensitivity and blood sugar stability. They tended to get diseases that killed the younger mice, such as various forms of cancer, at far more advanced ages. Gene expression experiments showed fewer changes in the activity of genes associated with inflammation, metabolism and aging in the long-lived animals compared to the shorter-lived ones.

Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.

γδ T cells are a unique and poorly understood class of lymphocytes generally regarded for their role in barrier protection with functionally distinct subpopulations residing in epithelial tissues, including those of the skin, gut, and lung. In addition to responding to antigen presentation via the T cell receptor, similar to conventional T cells (regulatory, helper, and cytotoxic T cells) of the adaptive immune system, γδ T cells can respond directly to cytokines and other intact proteins without antigen processing and presentation, and have the capacity to phagocytize much like innate immune cells.

In adipose tissues, contrary to their traditional function in infection control, γδ T cells appear to play major roles in maintaining homeostasis with respect to inflammation and insulin sensitivity. Adipose tissue γδ T cells have been shown to increase in number in mouse models of diet-induced obesity, where they promote macrophage accumulation, inflammation, and insulin resistance. More recently, they were reported to regulate adipose tissue regulatory T cell homeostasis and thermogenesis in adolescent and young-adult mice.

Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in visceral adipose tissue. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in visceral adipose tissue contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

Dormant non-proliferative neuronal precursors (dormant precursors) are a unique type of undifferentiated neuron, found in the adult brain of several mammalian species, including humans. Dormant precursors are fundamentally different from canonical neurogenic-niche progenitors as they are generated exquisitely during the embryonic development and maintain a state of protracted postmitotic immaturity lasting up to several decades after birth. Thus, dormant precursors are not pluripotent progenitors, but to all effects extremely immature neurons. Recently, transgenic models allowed to reveal that with age virtually all dormant precursors progressively awaken, abandon the immature state, and become fully functional neurons.

Compelling evidence implies that dormant precursors in the adult brain are physiologically relevant and may contribute to an overlooked form of late brain maturation. Intriguingly, our brain seems to use this resource sparingly throughout the whole course of life. To fully understand the contribution of dormant precursors integration, it will be crucial to identify the molecular mechanisms promoting or hindering maturation and the behavioral impacts.

Considering the possibility of a precursor-based contribution to learning and adaptation of input processing in the young individuals may shed a new light on development. The handful of dormant precursors still available up to an advanced age may also constitute a precious resource and understanding the mechanisms that promote their late integration could allow to recover every last bit of untapped potential, perhaps improving cognition and/or adaptation in the aging brain. Importantly, the number of dormant precursors is inherently limited by their non-proliferative nature and purposely promoting their integration in early life will lead to their premature exhaustion. Therefore, a comprehensive understanding of the relevance of dormant precursors in processes of brain maturation and adaptation along the different life phases constitutes a pressing need.

SIRT6 has a range of post-translational modification (PTM) capabilities and is widely involved in aging, immunity, and cancer regulation. SIRT6 is a longevity protein that prevents cells, tissues, organs, and the body from aging. Although the mechanisms underlying these effects are diverse, they all involve resistance of aging by promoting of DNA damage repair, maintaining of the normal telomere structure of chromosomes, regulating of glucose and NAD+ metabolic balance, and by regulating of the senescence-associated secretory phenotype (SASP). SIRT6 can also affect the differentiation and function of immune cells by regulating PTM affecting cells or the immunometabolism. However, the role of SIRT6 in immune regulation is complex.

Although most studies have shown SIRT6 to have anti-inflammatory activity, there is no lack of evidence regarding its pro-inflammatory potential. There has been insufficient research on how SIRT6 affects inflammation by regulating immune cells; SIRT6 has rarely been studied in many immune cells including granulocytes, monocytes, B cells, natural killer (NK) cells, and NKT cells. However, according to the recent research, the SIRT6-PTM or immunometabolism axes represent new directions with research potential.

The role of SIRT6 in cancer development is complex. SIRT6 shows differential expression in cancer tissues compared with normal tissues; its expression levels may also vary among different cancers, at different stages of the same cancer, and in different cell lines of the same tumor type. It also has both positive and negative effects on the regulation of cancer. Few studies have analyzed whether SIRT6 could achieve anti-cancer effects via regulation of immune cell function. This could represent a new direction for future research. For example, it may be possible to adjust the polarization of macrophages through SIRT6 to affect tumor progression.

Taken together, these findings indicate that SIRT6 will serve as an important target candidate for regulating immunosenescence and immune cell function. Drugs designed to target SIRT6 will also make an important contribution to the fight against chronic inflammation and cancer. SIRT6, as an important regulator throughout immunosenescence, inflammaging, and cancer, is a potential target for the regulation of the immune system.

As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient.

It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice.

Chaperone treatment increased phosphorylated CREB (p-CREB), which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone-treated aged mice. Further, hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p-CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging.

Aging is a multifaceted and complicated process, manifested by a decline of normal physiological functions across tissues and organs, leading to overt frailty, mortality, and chronic diseases, such as skeletal, cardiovascular, and cognitive disorders, necessitating the development of practical therapeutic approaches.

Stem cell aging is one of the leading theories of organismal aging. For decades, mesenchymal stem/stromal cells (MSCs) have been regarded as a viable and ideal source for stem cell-based therapy in anti-aging treatment due to their outstanding clinical characteristics, including easy accessibility, simplicity of isolation, self-renewal, and proliferation ability, multilineage differentiation potentials, and immunomodulatory effects. Nonetheless, as evidenced in numerous studies, MSCs undergo functional deterioration and gradually lose stemness with systematic age in vivo or extended culture in vitro, limiting their therapeutic applications.

Even though our understanding of the processes behind MSC senescence remains unclear, significant progress has been achieved in elucidating the aspects of the age-related MSC phenotypic changes and possible mechanisms driving MSC senescence. In this review, we aim to summarize the current knowledge of the morphological, biological, and stem-cell marker alterations of aging MSCs, the cellular and molecular mechanisms that underlie MSC senescence, the recent progress made regarding the innovative techniques to rejuvenate senescent MSCs and combat aging, with a particular focus on the interplay between aging MSCs and their niche as well as clinical translational relevance. Also, we provide some promising and novel directions for future research concerning MSC senescence.

As a paradigm of successful human aging, long-lived individuals (LLIs) achieve extreme old age without developing serious age-related diseases (e.g., cardiovascular disease, neurodegenerative disorders, and cancer). Gene expression is thought to have a close association with the activity of processes involved in healthy aging and longevity in LLIs. Here, to find the processes displaying reduced biological activities in long-lived people, we obtained and analyzed the transcriptomes of peripheral white blood cells from 193 female LLIs and 83 gender-matched spouses of LLI children (F1SPs) from two independent Chinese longevity cohorts.

Results showed that genes related to the ribosome pathway, especially ribosomal protein genes (RPGs), were significantly down-regulated in the LLIs. We also found that most of the RPGs were positively coexpressed with the ETS1 gene, which was down-regulated in LLIs. This gene encodes a transcription factor that binds to RPG promoters, and its down-regulation leads to the reduced RPG expression. Furthermore, knockdown of ETS1 alleviated cellular senescence and suppressed RPG transcription in human dermal fibroblast (HDF) and human embryonic lung fibroblast (IMR-90) cells.

Thus, these findings reveal that decreased ribosome biogenesis caused, at least in part, by the down-regulation of ETS1 exists in certain female LLIs and may contribute to healthy aging and life span extension in long-lived people.

"I wondered why cells allow damage to build up in the first place. And the idea came to me then, which was the realisation that it takes energy to combat the build-up of damage. There are maintenance and repair processes, proofreading mechanisms to make sure you don't do things wrong in the first place, and then clearance mechanisms to make sure you clean up your mistakes and get rid of them. And all of that costs energy."

"I started thinking that maybe this was the answer to question of why we age and die - because it was never evolutionarily worthwhile to invest enough in the maintenance and repair processes of the body to keep our cells from going on indefinitely. The essence of the theory is simply that, under the pressure of natural selection, organisms invest enough in the maintenance of somatic cells to keep them going for long enough to allow us to grow and reproduce and make the next generation, but it was never worthwhile for them to invest enough for those cells to last indefinitely."

"The theory says that aging will occur, because the whole repertoire of maintenance and repair systems will be tuned to a level that allows damage to build up. That has interesting implications in that it tells us that, from an evolutionary perspective, we should not expect there to be a single mechanism of aging. Very often you'll find groups of scientists that are championing one or other mechanism - so it's all telomeres, or it's all DNA mutations, or proteostasis collapse, or mitochondria, or cellular senescence. But the theory tells us is that it is not one mechanism versus another mechanism but that they work simultaneously, and they work in synergistic ways."

Persistent hypertension can cause long-lasting changes in the structure of vascular smooth muscle cells (the cells making up the walls of blood vessels) through a process called "vascular remodeling." If left unchecked, this restructuring can stiffen arterials walls, which lose their ability to adjust their size appropriately. This, in turn, leads to arteriosclerosis and increases the risk of cerebrovascular disease.

Why and how hypertension triggers vascular remodeling is not entirely clear. Scientists have shown that macrophages, a type of white blood cells that kill foreign bodies, are involved in the transformation. Specifically, the macrophages accumulate within blood vessel walls from outside the vessels and cause chronic inflammation. However, the underlying mechanism that orchestrates this process remains unknown.

A new study recently investigated a mechanism known as "excitation-transcription (E-T) coupling" in vascular smooth muscle cells. Although E-T coupling occurs in vascular smooth muscle cells after an influx of Ca2+ under high pressure, not much was known about how it happens, what genes are triggered, and the role it plays in our bodies.

By taking a detailed look at the genes promoted by E-T coupling and observing their effects when blocked or amplified, the researchers made some important discoveries. Firstly, some of these genes were related to chemotaxis, the phenomenon by which cells movement is triggered and directed by chemical stimuli. This helped explain the accumulation of macrophages in blood vessel walls from outside the vessels. Additionally, these genes promoted the remodeling of the medial layer of arteries, where vascular smooth muscle cells reside and control blood flow through contraction and expansion. "Taken together, our results explain how E-T coupling caused by high pressure in vascular smooth muscle cells can modulate macrophage migration and subsequent inflammation, altering the vascular structure,"

The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6.

MDPs have been extensively studied in the context of aging. Three MDPs have been studied in the context of age-related diseases: humanin, MOTS-c, and SHLP2. Humanin has been shown to mitigate Alzheimer's disease pathology in rodents, and its levels and genetic variation associate with age and cognition. MOTS-c has been described as an exercise mimetic and prevents muscle atrophy in mice, and its levels and genetic variation associate with age and type 2 diabetes (T2D). SHLP2 functions as a mitochondrial modulator and protein chaperone, and its levels associate with age and prostate cancer.

In addition to their ability to attenuate age-related diseases, MDPs have promoted lifespan and healthspan. Humanin is the best-conserved MDP and is found in as diverse species as humans, naked mole rats, and nematodes. Overexpression of humanin increased lifespan in nematodes, and this was dependent on FOXO. Additionally, humanin has increased autophagy in cells, and this increase in autophagy was also required for the lifespan extension in the transgenic worms. The second approach was to initiate a longevity experiment in mice in which we injected middle-aged (18-month-old) female mice with humanin twice a week. Although lifespan was not increased - likely because of humanin's short half-life of approximately 20 minutes - healthspan measures such as memory and metabolic parameters improved. Thus, humanin is sufficient to increase lifespan and healthspan in model organisms, and an optimized dosing of humanin may lead to increases in lifespan in more complex organisms.

"Cellular exercise" is a concept where low levels of cellular stress, induced by chronic calorie restriction or physical exercise, can lead to molecular adaptations on the cellular level that can protect the body from cancer and cardiovascular disease. An increase in reactive oxygen species induced by caloric restriction and physical exercise can produce improvements in redox equilibrium that can result in a more adaptive capable cell.

Insulin-like growth factor-1 has a dual effect wherein calorie restriction downregulates insulin-like growth factor-1 inhibiting pathways of carcinogenic proliferation and metastasis and physical exercise can upregulate insulin-like growth factor-1 to promote mitochondrial biogenesis and protein synthesis, thereby strengthening the healthy muscle tissue in opposition to hypoxic ischemic damage and improving muscular regenerative properties. Transcription of Nrf2 is also upregulated to attenuate inflammation induced by nuclear factor-κB, AMPK upregulates genes through PGC-1α to prevent sarcopenia and induce lipolysis.

This molecular melody is the complex composition that explains the cellular adaption that occurs to strengthen the body from cognitive dysfunction, cardiometabolic failure and carcinogenic implantation and metastasis via mechanisms of redox equilibrium, oxidative protection, attenuation of inflammation, and attenuation of carcinogenic proliferation and growth.