Fight Aging! Newsletter, November 28th 2022

The super-rich eventually reach a point where having more money doesn't improve their lives very much. "If you buy a yacht, you can always get a bigger yacht; if you buy a plane, you can always get a bigger plane. But the extent to which your life is changing with more money is actually very minimal." It makes more sense to direct funds to being healthier and living longer. Such deep-pocketed individuals and groups are looking to be the biggest investors in longevity research. Most of the 4.4 billion invested over the last five years into understanding whether or not reprogramming our cells might help us live longer has gone into Altos Labs, a biotech company whose funders are thought to include Jeff Bezos and Yuri Milner.

A sense of hope and optimism was palpable at the Longevity Investors Conference. I got the impression that most people believed that, with enough funding, positive scientific results were just a few years away. And with that, we'd be on the road to reliably extending human healthspan. The presenters were a mix of longtime academics, biotech startups, and people selling the idea of longevity as a high-end luxury good for those who frequent spas and lavish retreats. Some have been studying the biology of aging for decades, and are well-respected among their peers. But I also met a young man who told me that breathing low-oxygen air could benefit multiple aspects of my health - and who then commented that he "didn't believe" in covid vaccines. A 67-year-old man took to the stage to tell us that, since he'd been taking his own supplement, his biological age had reversed, and he was now biologically only 49 years old.

How is an investor - or anyone else, for that matter - meant to make sense of all these claims? Ask an academic, and they'll tell you that the answer is education-the more people know about the biology of aging and how clinical trials work, the better placed they are to work out how much faith to put in any claim. Many agree that it's the wild claims made by some - claims that we could live to be a thousand years old, or avoid death entirely - that have helped bring attention and investment to the field. But they have also tarnished its reputation as a scientific discipline.

Others say that while there's more hype in biotech than academia, they thinks that any hype tends to be short-lived. "If you're selling hot air, you can't get away with doing that for very long." I've been writing about the science of aging for over a decade myself, and I'm not sure I fully agree with him. I've seen shoddy science get plenty of press attention. I've seen smart scientists fall prey to flimsy claims about health-extending supplements. But I've also seen some fascinating and tantalizing research - enough to want to follow it through and find out if these approaches really will be as beneficial for people as they are for lab animals.

"Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach." The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids, and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called "glutamine addiction," but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine.

"DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut. We added chemical groups, called promoieties, to DON that rendered it inactive in the body until it reached the tumor, where the promoieties were clipped off by enzymes that are abundant in the tumor but not in the gut."

6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues.

In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

Brain aging is a significant cause of most neurodegenerative diseases and is often irreversible and lacks an effective treatment, leading to a dramatic decline in quality of life. As with other organ systems, brain function gradually declines during the aging, mainly in learning and memory functions. Some studies point out that age-related cognitive decline is characterized by a considerable reduction or even death of neurons in the brain. In the hippocampus (and perhaps in other brain areas), neuronal death can partially compensated by neuronal generation. However, neuronal production is significantly impaired with age. In the adult mammalian hippocampus, new neurons are derived from the stem cell and progenitor cell divisions, a process known as adult neurogenesis.

In recent years, evidence has accumulated that neurogenesis can restore a more youthful state during aging. In addition, increased adult neurogenesis contributes to a variety of human diseases, including cognitive impairment and neurodegenerative diseases. Neuroinflammation has been shown to alter neurogenesis in adults. Various inflammatory components, such as immune cells, cytokines, or chemokines, regulate neural stem cells' survival, proliferation, and maturation. During normal brain aging, increased inflammatory activity is caused by the activation of glial cells.

It has been shown that mesenchymal stem cells (MSCs) can stimulate neurogenesis and angiogenesis and delay neuronal cell death. At the same time, their secreted exosomes are smaller in size and cause less immune response in the body, which is a hot topic of current research. This manuscript describes how MSCs and their derived exosomes promote brain neurogenesis and thereby delay aging by improving brain inflammation.

Increasing evidence reports the benefits yielded by regular physical activity (PA) on the motor function in older people by preserving mobility, muscle strength, and balance. However, there is a methodological limitation that PA are evaluated at single time-point (primarily the baseline level) or short time-scales without considering the long-term dynamic nature of PA behavior. Group-based trajectory modeling (GBTM) allows grouping of subjects presenting with similar baseline values and longitudinal patterns of change according to their direction and magnitude. Using this method, some studies have detected different PA trajectories among older adult cohorts. Three studies examined the association of PA trajectories with mortality in older adults. But, there isn't an investigation of the temporal association of long-term PA participation trajectories with subsequent motor function changes and incident frailty.

Therefore, the main objectives of this study were to investigate different trajectories of long-term PA participation over a 6-year span by the GBTM and evaluate their associations with subsequent motor function decline and incident frailty in middle-aged and elderly adults. Our hypotheses are that older adults maintaining PA over time will have a slower motor function decline and a lower risk of incident frailty compared with persistently inactive subjects or those reducing PA levels, and that increasing PA even at older ages promotes healthy aging characterized by reduced motor function decline and incident frailty.

Five distinct trajectories of long-term PA participation were identified in the aging cohort, including persistently low-active trajectory (N = 2,039), increasing active trajectory (N = 1,711), declining active trajectory (N = 216), persistently moderate-active trajectory (N = 2,254), and persistently high-active trajectory (N = 2,007). Compared with the persistently low-active group, the participants in persistently moderate- and high-active groups experienced significantly decelerated grip strength decline, decreased gait speed decline, and faster chair rises after multiple-adjustment. Similarly, participants maintaining moderate- and high-active PA were also associated with a lower risk of incident frailty (multiple-adjusted hazard ratio 0.70 and 0.42 respectively), compared with those with persistently low PA. Notably, the participants with the increasing active trajectory got similar health benefits as those with persistently moderate and high levels of PA.

Thus in conclusion, in addition to persistent PA, increasing PA was linked to a slower decline in motor function and lower risk of incident frailty in the cohort. Our findings suggest that regular PA is never too late.

Researchers modeled the relationship between biological age and grip strength of 1,274 middle aged and older adults using three "age acceleration clocks" based on DNA methylation, a process that provides a molecular biomarker and estimator of the pace of aging. The clocks were originally modeled from various studies examining diabetes, cardiovascular disease, cancer, physical disability, Alzheimer's disease, inflammation, and early mortality. Results reveal that both older men and women showed an association between lower grip strength and biological age acceleration across the DNA methylation clocks. The real strength of this study was in the eight to 10 years of observation, in which lower grip strength predicted faster biological aging measured up to a decade later.

Past studies have shown that low grip strength is an extremely strong predictor of adverse health events. One study even found that it is a better predictor of cardiovascular events, such as myocardial infarction, than systolic blood pressure - the clinical hallmark for detecting heart disorders. Researchers have previously shown a robust association between weakness and chronic disease and mortality across populations. This evidence coupled with the recent findings shows potential for clinicians to adopt the use of grip strength as a way to screen individuals for future risk of functional decline, chronic disease and even early mortality.

Future research is needed to understand the connection between grip strength and age acceleration, including how inflammatory conditions contribute to age-related weakness and mortality. Previous studies have shown that chronic inflammation in aging - known as "inflammaging" - is a significant risk factor for mortality among older adults. This inflammation is also associated with lower grip strength and may be a significant predictor on the pathway between lower grip strength and both disability and chronic disease multimorbidity.

Age-associated microglial dysfunction contributes to the accumulation of amyloid-β (Aβ) plaques in Alzheimer's disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer's disease. Here we found that naturally aged microglia phagocytosed less Aβ over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Aβ.

Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Aβ phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Aβ uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Aβ phagocytosis that likely underlies the progression to neurologic disease.

A recent study tested the possibility that altered mechanosensing of the extracellular environment, i.e., the extracellular matrix (ECM), is a signal for physiological aging. The transcriptional coactivators and end effectors of the Hippo signaling pathway, YAP and TAZ, are established mediators that link mechanosensation to changes in cell behavior through the regulation of transcriptional programs.

To explore the hypothesis that YAP/TAZ mediate effects of aging, the authors first performed a series of experiments employing single-cell RNA-seq data that indicated the downregulation of a YAP/TAZ activation signature gene set in dermal fibroblasts of old mice. This pattern of depressed YAP/TAZ activity was also observed in other stromal cells (e.g., kidney fibroblasts) as well as contractile cells (cardiomyocytes, vascular smooth muscle cells) but not in epithelial cells, hepatocytes, or lymphocytes, indicating cell-type specificity.

Depletion of YAP/TAZ in young mice reduced dermal fibroblast number and phenocopied aged skin in control mice. Targeted deletion of YAP/TAZ in vascular smooth muscle cells elicited aortic dissection, rupture, and death in several weeks, thereby accelerating aging-associated pathology. To further substantiate YAP/TAZ regulation of cellular senescence, transcriptome profiling in freshly isolated dermal fibroblasts from young mice demonstrated increased senescence-associated secretory phenotype (SASP) genes as well as increased β-gal expression, both hallmarks of senescence, in YAP/TAZ deficient cells. On the other hand, supplementing YAP to fibroblasts cultured from old mice led to suppression of SASP and β-gal positivity.

cGAS-STING signaling modulates innate immune responses and has been previously implicated in the regulation of senescence. Through multiple complementary approaches, researchers showed that YAP/TAZ suppressed cGAS activation in several cell and tissue types, and involved the inappropriate release of genomic DNA into the cytosol. How does YAP/TAZ restrain cGAS-STING? The authors astutely recognized a relationship between decreased YAP/TAZ activity and distorted nuclear architecture in old cells. Moreover, the addition of active YAP rescued abnormal nuclear structure caused by aging. Additional screens revealed that YAP/TAZ directly promote the expression of two key factors that maintain proper nuclear envelope integrity, lamin B1 and ACTR2.

These findings demonstrate that YAP/TAZ is a critical upstream modulator of nuclear integrity and functions in young cells to keep cGAS-STING in check to prevent the aging phenotype of cellular senescence.

Regular physical activity (PA) promotes healthy aging, and activities aiming to increase muscular strength (i.e., resistance exercise, RE) are important PA modalities for achieving health benefits. Previous meta-analyses demonstrated that both RE and muscular strength were associated with mortality benefits, even when RE was performed above the PA targets recommended by current guidelines.

While optimal volumes of endurance-type exercise (aerobic moderate-to-vigorous PA, MVPA) to reduce mortality from all causes have been suggested to amount to or even exceed 700 minutes per week, recent meta-analyses suggest that large amounts of RE may be associated with adverse outcomes. Although these analyses demonstrated an overall inverse association between RE and mortality risk from all causes and/or from cardiovascular diseases (CVD), diabetes, and cancers, this was only true up to a certain threshold of RE volume per week (i.e., there is a U-shaped dose-response relationship between RE and mortality). Should the many individuals engaging in RE volumes exceeding the reported cutoffs for optimal benefits be worried?

Overall, excessive RE may put a small number of individuals at a higher risk for adverse health outcomes, which is similar to the effect of extreme endurance exercise. This risk may vary with age and sex (e.g., while young subjects may be more susceptible than older ones to arterial stiffness following RE, men are much more likely than women to be injured performing RE) and can increase with inappropriate execution of RE, overconfidence, and/or subtle pre-existing comorbidities.

Although low-to-moderate intensity RE is usually well tolerated and widely recommended for individuals with and without cardiovascular disease, heart rate and systolic blood pressure values in cardiac patients are higher during low-intensity as compared to high-intensity RE. As low-intensity RE is typically performed at higher volumes than high-intensity RE, vulnerable individuals performing high volumes of low-intensity RE might be at higher mortality risk than previously assumed.

The inflammatory environment characteristic of the aged brain is caused by activation of glial cells, mainly microglia. Several studies report that neuroinflammation leads to reduced gonadotropin-releasing hormone (GnRH) secretion, which is associated with multiple aging-related physiological changes, including bone loss, skin atrophy, muscle weakness, and memory loss. Indeed, GnRH administration amend aging-impaired neurogenesis and decelerates aging in mice. In addition, the same authors also describe that inhibition of NF-κB-directed immunity, specifically in hypothalamic microglia cells, has an anti-aging effect.

GnRH secretion is regulated by hormonal and environmental signals such as kisspeptin. This peptide plays a critical role in controlling the onset of puberty and reproductive function in adulthood. There are two populations of kisspeptin neurons, one in the anteroventral periventricular nucleus (AVPV) and one in the arcuate nucleus (Arc), that are targets of positive and negative feedback regulation of estrogen, respectively. Aging female rats transition from regular to irregular estrus cycles, constant estrus, and finally to an anestrus stage. Changes within the hypothalamic-pituitary-ovarian axis, manifested by altered secretion of neurotransmitters, altered secretion of pituitary hormones and altered follicular development and steroid content, lead to the final cessation of reproductive cycles. These processes that lead to reproductive senescence are associated with an increase in circulating cytokines and proinflammatory markers produced by microglial cells. Indeed, several studies describe that hypothalamic and systemic inflammation affect kisspeptin neurons, which are responsible for regulating GnRH neurons.

IGF1 is a neurotrophic factor with an outstanding neuroprotective action in the central nervous system. Previous studies of our group showed that intraparenchymal hypothalamic IGF1 gene therapy was capable to prolong the operation of reproductive cycles in rats. Indeed, we have demonstrated that intracerebroventricular IGF1 gene therapy restores motor performance and generates cognitive and morphological changes in the dorsal hippocampus in senile rats. In addition, we have reported that IGF1 gene therapy modifies microglia number and phenotype in senile rats and decreases astrocytic inflammatory response in vitro, supporting the extensive idea that IGF1 plays a potent anti-inflammatory effect.

The aim of the present study is to investigate the effect of IGF1 gene therapy on estrous cycle, kisspeptin, and GnRH neurons, and microglial cells in middle-aged female rats. Our data indicate that IGF1 gene therapy prolongs the operation of reproductive cycles in middle-aged rats by modulating kisspeptin/GnRH secretion in the hypothalamus and altering microglial cell number and reactivity. Based on our findings, we propose IGF1 gene therapy to delay reproductive senescence as a potential strategy to optimize lifespan and combat age-related health problems in women.

Medin belongs to the group of amyloids. Of these proteins, amyloid-β is best known because it clumps together in the brains of Alzheimer's patients. These aggregates then deposit both as so-called plaques directly in the brain tissue, but also in its blood vessels, thereby damaging the nerve cells and the blood vessels, respectively. But while many studies have focused on amyloid-β, medin has not been a focus of interest.

However, medin is actually found in the blood vessels of almost everybody over 50 years of age, making it the most common amyloid known. Medin even develops in aging mice. The older the mice get, the more medin accumulates in the blood vessels of their brains. What's more, when the brain becomes active and triggers an increase in blood supply, vessels with medin deposits expand more slowly than those without medin. This ability of blood vessels to expand, however, is important to optimally supply the brain with oxygen and nutrients.

Now researchers were able to show in Alzheimer's mouse models that medin accumulates even more strongly in the brain's blood vessels if amyloid-β deposits are also present. Importantly, these findings were confirmed when brain tissue from organ donors with Alzheimer's dementia was analysed. However, when mice were genetically modified to prevent medin formation, significantly fewer amyloid-β deposits developed, and as a result, less damage to blood vessels occurred. "There are only a handful of research groups worldwide working on medin at all. We have now been able to show through many experiments that medin actually promotes vascular pathology in Alzheimer's models, and this indicates that medin is one of the causes of the disease."

The gut microbiome is a modifier of disease risk because it interacts with nutrition, metabolism, immunity, and infection. Aging-related health loss has been correlated with transition to different microbiome states. There is broad consensus how the microbiome changes with age, but specific intervention targets are less clear. Moreover, terms like diversity, assumed by many to be desirable, and 'uniqueness', which has been cast as a marker of healthy aging, need greater precision and should not be used agnostic of the loss or gain of specific taxa in aging. Other summary statistics include different measures of uniqueness that capture specific aspects of gut microbiome variability and are calculated using different distance measures.

This study explored whether determining the gain or loss of specific taxa represent a more precise metric of healthy/unhealthy aging than summary microbiome statistics, such as diversity and uniqueness. We analyzed microbiome diversity and four measures of microbiome uniqueness in 21,000 gut microbiomes for their relationship with aging and health. We show that diversity and uniqueness measures are not synonymous; uniqueness is not a uniformly desirable feature of the aging microbiome, nor is it an accurate biomarker of healthy aging. Different measures of uniqueness show different associations with diversity and with markers of health and disease.

The study identifies that the gut microbiome alterations associated with both aging in general and unhealthy aging are characterized by a common theme: loss of the core microbiome structure (specifically a coabundant species-level guild of the core microbiome) and concomitant increase of a specific guild of disease-associated taxa.

The study that is most often cited as evidence that metformin slows the aging process in humans was released with a press release misleadingly titled "Type 2 diabetics can live longer than people without the disease." But the underlying study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients with poorer glycemic control (those on other drugs) and a random assortment of the nondiabetic population - and then systematically pushed subjects on metformin "off the books" as soon as their diabetes progressed.

The same problem (or related ones) have plagued most of the observational studies that you may have heard cited as showing that metformin lowers the risk of atherosclerosis, total mortality, and especially cancer. Drawing inferences from such studies about effects on aging in otherwise-healthy people would thus be misguided even if these studies didn't share this design flaw, since none of these other studies include a separate group of people without diabetes. Rather, such studies have compared metformin-taking diabetic people to other people with diabetes taking other diabetic drugs. But actually, even in such diabetics-only studies, the apparent benefits of metformin vanish when the studies are designed to avoid survivorship bias and selection bias.

When put to the test in human trials, metformin has no effect on blood sugar control in obese women with normal glucose tolerance and only modest effects on fasting glucose in normal-weight, nondiabetic men. Similarly, exercise but not metformin tames glycemic variability (dangerously wide swings in blood sugar over the course of the day) in prediabetic people. And importantly, adding metformin to such lifestyle interventions doesn't lower the risk of developing diabetes any more than lifestyle all by itself.

You may be surprised to learn that there has already been a trial with followup that gives fairly long-term human data on mortality in a group of people who were not yet diabetic - and again, metformin came up short. This was report from the long-term follow-up of the Diabetes Prevention Program (DPP). The volunteers in the DPP were on average 50 years old, and all had prediabetes. The DPP itself lasted only 2.8 years, but the researchers followed up with the participants at 10, 15, and as much as 20 years later. And to get to the punchline, people who had been taking metformin lived no longer than people in the control group.

Researchers found in cells and in mice that a low-protein diet blocked the nutrient signaling pathway that fires up a master regulator of cancer growth. The regulator, mTORC1, controls how cells use nutritional signals to grow and multiply. It's highly active in cancers with certain mutations and is known to cause cancer to become resistant to standard treatments. A low-protein diet, and specifically a reduction in two key amino acids, changed the nutritional signals through a complex called GATOR.

GATOR1 and GATOR2 work together to keep mTORC1 in business. When a cell has plenty of nutrients, GATOR2 activates mTORC1. When nutrients are low, GATOR1 deactivates mTORC1. Limiting certain amino acids blocks this nutrient signaling. Previous efforts to block mTORC1 have focused on inhibiting its cancer-causing signals. But these inhibitors cause significant side effects - and when patients stop taking it, the cancer comes back. The study suggests that blocking the nutrient pathway by limiting amino acids through a low-protein diet offers an alternative way to shut down mTORC1.

Researchers confirmed their findings in cells and mice, where they saw that limiting amino acids stopped the cancer from growing and led to increased cell death. They also looked at tissue biopsies from patients with colon cancer, which confirmed high markers of mTORC correlated with more resistance to chemotherapy and worse outcomes.

Frailty is a highly prevalent geriatric syndrome that has attracted significant attention from physicians and researchers due to its associated increase in vulnerability and healthcare costs, especially in the elderly population. Generally, frail patients suffer from multiple chronic diseases, with comorbidities and polypharmacy greatly challenging their health management. Gerontologists suggest that targeting the common pathogenesis of comorbidities rather than a single disease is probably a better solution for older people. Multiple factors contribute to development of frailty with advancing age, thus the therapeutic target is diversed depends on specific condition. Nutrition supplements and physical exercise are proved to be helpful in preventing and treatment of frailty, however, valid pharmaceutical intervention is scarce.

Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties, offering a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy is undergoing phase I and II trials in human subjects to endorse the safety and efficacy of MSCs for aging frailty.

Numerous studies have shown that rapamycin and rapalogs, considered novel and promising longevity agents, can extend lifespan. Interestingly, these agents showed an immunosuppressive effect at high doses and an immune stimulatory effect at low doses. However, the reason for these immunity-boosting effects is unclear. The inhibition of mammalian target of rapamycin (mTORC1) is a possible explanation, as mTOR can regulate the STAT signaling pathway. A study showed a significant difference in STAT phosphorylation levels in the T cells of healthy people compared with unhealthy senescent people.

Senolytics are a novel type of agent. The interference of stem cell signaling pathways temporarily disables the senescent cell anti-apoptotic pathway (SCAP), thus targeting selectively senescent cells. In addition to its main effect on clearing senescent cells, senolytics can also eliminate pro-inflammatory cytokines. According to the study, inflammation symptoms are relieved after the administration of senolytics. A recent study found reduced SASP and coronavirus-related mortality in old mice after the administration of senolytics.

A low level of nicotinamide adenine dinucleotide (NAD)+ is reportedly associated with the poor function of mitochondria and metabolic reprogramming of immune cells; therefore, NAD+ is also recognized as a therapeutic target for aging immunity. Promising data has demonstrated that administrating nicotinamide mononucleotide, the NAD+ precursor, into mice could maintain NAD+ levels and mitochondrial function, with the mitochondrial function of immunocytes being essential for controlling virus propagation.

A centenarian study revealed that longevity is associated with gut microbial structures, making individuals more potent against age-associated disorders and leading to a longer life. The microbiota-targeting probiotic and dietary interventions affect natural aging by enhancing oxidation resistance, regulating metabolism, suppressing chronic inflammation, and promoting immune homeostasis. Immunosenescence may have a certain influence on human microbial composition, function, and diversity. In addition, fecal microbiota transplantation or prebiotic/probiotic/synbiotic supplementation in the diet is beneficial for restoring active microbiota and extending a healthy lifespan. Thus, there are multiple ongoing developments in this field to ease the process of aging and reduce the risk of potential disabilities that could lead to a significant decrease in the quality of life of elderly individuals.