Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon-myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages - important representatives of the innate immune system - are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging. Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses.

Here we examine the role of cytotoxic CD8+ T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases but understudied in the aging CNS. We show that accumulation of CD8+ T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8+ T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes.

Mechanistically, we provide evidence that CD8+ T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8+ CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function.

Six patients with dementia traveled to Mexico last year to be injected with a gene therapy not authorized for use in the U.S., according to the CEO of a Seattle-area startup that wants to accelerate testing of unproven anti-aging medicines and views U.S. drug safety regulations as a hindrance. At the heart of the project is a controversial biotech called BioViva, whose CEO had herself injected with an experimental gene therapy in Colombia and whose advisory board includes renowned Harvard geneticist George Church. It is part of a growing ecosystem of entrepreneurs and scientists, dreamers and schemers, who believe aging is not inevitable and aim to develop treatments to extend the human life span.

Last month, during a talk hosted by the National University of Singapore, the CEO, Elizabeth Parrish, divulged that she was eagerly awaiting data from a human study involving six patients who received an experimental gene therapy. On Friday, she told STAT the procedures were done last year in Mexico. If true, it would be the first known attempt to use the technique to treat age-related dementia, which is most often caused by Alzheimer's disease.

STAT set out to independently verify the accuracy of Parrish's claims. While many key details could not be confirmed, including the identities of these six patients and how the purported treatment affected them, STAT found evidence that BioViva and partners were recruiting patients. A newsletter emailed by BioViva in 2019 said 10 patients over age 50 with mild to moderate Alzheimer's were needed for a study of a gene therapy. The one-hour procedure, according to an FAQ linked from the email, would be done in Mexico City and involved a one-time injection. The effort raises the specter of an overseas medical tourism industry targeting patients desperate to lengthen their lives and offering unproven treatments that would permanently alter the genetic code inside recipients' cells.

The microbiome plays a fundamental role in the maturation, function, and regulation of the host immune system from birth to old age. In return, the immune system has co-evolved a mutualistic relationship with trillions of beneficial microbes residing our bodies while mounting efficient responses to fight invading pathogens. As we age, both the immune system and the gut microbiome undergo significant changes in composition and function that correlate with increased susceptibility to infectious diseases and reduced vaccination responses. Emerging studies suggest that targeting age-related dysbiosis can improve health- and lifespan, in part through reducing systemic low-grade inflammation and immunosenescence - two hallmarks of the aging process. However, a cause and effect relationship of age-related dysbiosis and associated functional declines in immune cell functioning have yet to be demonstrated in clinical settings.

Given the ever-growing impact of the gut microbiome on the host immune system, it is reasonable to speculate that restoring age-related declines in gut microbial richness and function - be it through personalized nutrition or supplements - may represent a prophylactic measure to fight functional declines in immune fitness. In this context, prebiotics, probiotics, and postbiotics or synbiotics with the ability to reinforce immunity through supporting intestinal barrier integrity or by regulating inflammatory processes have been tested in clinical settings. However, a lack of consistency between studies, strain specific differences or doses, prebiotic nature and quantity, or age and medical conditions of the subjects have made it difficult to validate the effectiveness of such approaches to reinforce age-associated declines in host-immune fitness.

None the less, mining the gut microbiome is a treasure trove waiting to be unlocked, and gerontology is no exception here. As exemplified by numerous preclinical studies, restoration of a youthful microbiome has rejuvenating potential for the aged host through sustaining immunity and health-span. Thus, a better understanding of the dynamic age-related changes in gut microbial community structures and associated metabolome, how such alterations affect cellular immune networks and how these pathways can be therapeutically targeted will have wide-reaching implications for future strategies to reinforce or even rejuvenate the aging immune system.

Michael Greve, founder of the Forever Healthy Foundation and owner of Kizoo Technology Ventures, announced today that he will make available an additional 300 million to be invested in rejuvenation biotech. The funds, to be deployed via Kizoo, will be used to create and support more startups in the rejuvenation space. They will also allow Kizoo to maintain a strong commitment to its key startups during follow-up rounds and to advance the therapies from clinical development to public availability.

With this 300 million commitment, Greve and Kizoo double down on their mission to accelerate the advent of rejuvenation biotechnology by doing lighthouse investments in entirely new, repair-based approaches that treat the root causes of aging and thus overcome age-related diseases. Through the creation of successful companies, they seek to inspire scientists, investors, and the general public by demonstrating that human rejuvenation is not science fiction anymore and that the resulting therapies are affordable and uncomplicated.

Technologies pioneered by Kizoo's startups include removal of arterial plaque, decalcification of aged tissue, breaking of protein-glucose cross-links, and delivery of new mitochondria to aged cells - all aiming to prevent and repair common age-related conditions such as myocardial infarction, stroke, high blood pressure, tissue stiffening, skin aging, and loss of muscle function.

"I am really grateful that we can use the funds we have created with our highly successful technology ventures to contribute to the quest to get aging under full medical control and to make age-related diseases a thing of the past. For me, it is a worthy cause that is exciting in a technological, commercial, and above all, a humanitarian way." Greve expects that the new funds, in combination with the strong, multi-round commitment of Kizoo to its key startups, should trigger co-investments of up to 3-4 times the initial amount, resulting in a significant acceleration of the development and public availability of the therapies.

The fatty acid composition of biological membranes has been hypothesised to be a key molecular adaptation associated with the evolution of metabolic rates, ageing, and life span - the basis of the membrane pacemaker hypothesis (MPH). MPH proposes that highly unsaturated membranes enhance cellular metabolic processes while being more prone to oxidative damage, thereby increasing the rates of metabolism and ageing. MPH could, therefore, provide a mechanistic explanation for trade-offs between longevity, fecundity, and metabolic rates, predicting that short-lived species with fast metabolic rates and higher fecundity would have greater levels of membrane unsaturation.

However, previous comparative studies testing MPH provide mixed evidence regarding the direction of covariation between fatty acid unsaturation and life span or metabolic rate. Moreover, some empirical studies suggest that an n-3/n-6 PUFA ratio or the fatty acid chain length, rather than the overall unsaturation, could be the key traits coevolving with life span. In this study, we tested the coevolution of liver fatty acid composition with maximum life span, annual fecundity, and basal metabolic rate (BMR), using a recently published data set comprising liver fatty acid composition of 106 avian species.

While statistically controlling for the confounding effects of body mass and phylogeny, we found no support for long life span evolving with low fatty acid unsaturation and only very weak support for fatty acid unsaturation acting as a pacemaker of BMR. Moreover, our analysis provided no evidence for the previously reported links between life span and n-3 PUFA/total PUFA or MUFA proportion.

Our results rather suggest that long life span evolves with long-chain fatty acids irrespective of their degree of unsaturation as life span was positively associated with at least one long-chain fatty acid of each type (i.e., SFA, MUFA, n-6 PUFA, and n-3 PUFA). Importantly, maximum life span, annual fecundity, and BMR were associated with different fatty acids or fatty acid indices, indicating that longevity, fecundity, and BMR coevolve with different aspects of fatty acid composition. Therefore, in addition to posing significant challenges to MPH, our results imply that fatty acid composition does not pose an evolutionary constraint underpinning life-history trade-offs at the molecular level.

Skin wounds generally heal by scarring, a fibrotic process mediated by the Engrailed-1 (En1) fibroblast lineage. Scars differ from normal unwounded skin in three ways: (i) They lack hair follicles, sebaceous glands, and other dermal appendages; (ii) they contain dense, parallel extracellular matrix fibers rather than the "basket-weave" pattern of uninjured skin; and (iii) as a result of this altered matrix structure, they lack skin's normal flexibility and strength. A successful scar therapy would address these three differences by promoting regrowth of dermal appendages, reestablishment of normal matrix ultrastructure, and restoration of mechanical robustness. However, little is known about the cellular and molecular mechanisms blocking a regenerative healing response in postnatal skin, or whether these mechanisms can be bypassed by modulating specific fibroblast lineages.

We asked whether scarring fibroblasts are derived purely from expansion of existing En1 lineage-positive fibroblasts present in unwounded skin, or whether En1 scar fibroblasts could arise de novo by activation of En1 expression in postnatal, En1 lineage-negative fibroblasts within the wound niche. We used fibroblast transplantation as well as transgenic mouse models to trace En1 expression in a spatiotemporally defined fashion. Next, we studied fibroblast responses to mechanical forces in vitro and in vivo to establish a mechanotransduction mechanism linking skin tension to postnatal En1 expression. Finally, we used chemical (verteporfin) and transgenic inhibition of mechanotransduction signaling to modulate En1 expression during wound healing.

Fibroblast transplantation and lineage-tracing studies reveal that En1 lineage-negative fibroblasts (ENFs) of the reticular (deep) dermis activate En1 in the wound environment, generating ~40 to 50% of scar fibroblasts. This phenomenon depends on mechanical cues. Comparison of ENFs with En1-expressing and En1 knockdown fibroblasts by RNA sequencing suggests that En1 regulates a wide array of genes related to skin fibrosis. In healing wounds, YAP inhibition by verteporfin blocks En1 activation and promotes ENF-mediated repair, yielding skin regeneration in 30 days with recovery of functional hair follicles and sebaceous glands. This suggests that modulation of En1 activation, whether direct or indirect, can yield wound regeneration.

Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal somatic cells, which age and die. In this review, we describe the germline as clock-free and somatic cells as clock-bound and discuss aging with respect to three DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks.

The initiation of the DNA methylation aging clock, the telomeric clock, and perhaps other clocks at the beginning of development suggests an intimate relationship between development and aging. Indeed, the adaptation of developmental clock rate to environmental pressure could account for the wide variation in lifespan observed between species. For example, humans and naked mole-rats exhibit neoteny, where slowing the rate of development correlates with an extension of lifespan. The application of germline strategies in somatic stem cells has resulted in the remarkable regenerative capacity of lower life forms that are capable of indefinite lifespans, such as sponges, planarians, and hydra. This regenerative capacity has become increasingly restricted as more complex life forms evolved, being confined prior to the embryonic to fetal transition period in mammals. However, retention of extensive capacity for regeneration is observed in lower vertebrates, including fishes, amphibians, and reptiles, which also exhibit remarkable phenotypic plasticity in their capacity for metamorphosis and in certain cases of remarkable reversals of developmental stage and sexual development.

Finally, reprogramming using germline factors can uncover a similar but latent phenotypic plasticity in mammals by reverting both the developmental state and cellular age. Indeed, both natural phenotypic plasticity in the blue wrasse and partial reprogramming involve the repression of DNA methyl transferases and induction of demethylases which, by a yet-to-be-determined mechanism, may enable the DNA methylation clock to tick backward. The discovery that partial reprogramming can reverse the aging clock without permanent alteration of cellular identity has led to initial studies that demonstrate the potential to reverse organismic aging. Although there are many challenges ahead, our current understanding of cellular clocks and our ability to reprogram them using germline factors opens the door to many promising therapeutic approaches to slowing down, preventing, or reversing aging itself and thus treating the many age-related diseases that burden society. Indeed, if these approaches can be made practical and scalable, we may find ourselves in a future in which we have no time to age.

Growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, has recently received attention because of its numerous functions in modulating the development and differentiation of various tissues and organs. Studies regarding the role of GDF11 in the development of various diseases have been conducted in recent decades. GDF11 is reportedly beneficial with respect to controlling age-related cardiac hypertrophy, improving muscle tone, preventing degeneration in the central nervous system, enhancing cognitive function, and promoting tissue regeneration.

Important parabiosis experiments involving two animals of different ages, performed in 2013 and 2014, revealed that GDF11 levels were disrupted in an age-related manner in vascular, neurogenic, and skeletal muscle tissues. Those findings suggested that GDF11 may be regarded as an honorable "rejuvenation" factor that could restore regenerative function, thus resisting aging and extending longevity. A study in fish revealed that GDF11 has rejuvenation capacity to extend the lifespan. In 2020, a plasma proteomic dataset demonstrated that the GDF11 protein can significantly extend the lifespan.

These studies demonstrated critical roles for GDF11 in the inhibition of aging. However, recent studies have yielded conflicting data regarding the ability of GDF11 to alleviate dysfunction in age-related diseases. Thus, the regeneration ability of GDF11 with respect to age-related dysfunction requires further investigation. This review provides an overview of GDF11 and its functions in age-related diseases. It also discusses potential underlying mechanisms for the effects of GDF11 in age-related diseases.

Normal human cells do not divide indefinitely. When cultured in vitro, cells can undergo only a finite number of divisions before entering in a nondividing state, the so-called replicative senescence. Senescence has been suggested both as contribute and a consequence of the ageing process and is involved in the development of many age-related chronic diseases. Cellular senescence is a state of an irreversible growth arrest that occurs in response to various forms of cellular stress and is characterized by a pro-inflammatory secretory phenotype.

Multiple studies showed that cellular senescence occurs in both physiological and pathophysiological conditions. Senescent cells accumulate with ageing and can contribute to age-related decline in tissue function. Obesity is a metabolic condition that can accelerate the ageing process by promoting a premature induction of the senescent state of the cells. In contrast, caloric restriction without malnutrition is currently the most effective non-genetic intervention to delay ageing, and its potential in decreasing the cellular senescent burden is suggested.

The precise mechanisms underlying the effect of obesity in the induction of premature cellular senescence are poorly understood and warrant further investigation. Moreover, more studies are required to understand how lowering calories intake reduces cellular senescence burden, and whether this can directly lower levels of molecules involved in the inflammation process, like interleukins, which, for instance, could also be promoted by other variables independently altered by senescence. Plus, in obesity and ageing studies, the researchers tend to focus on one specific organ or pathology type, which limits the information that may be collected about the temporal biological order of senescence induction. Thus, more in vitro studies are required especially in cellular model systems that can replicate the alterations seen during in vivo progression in the ageing process.

By tracing individual neural stem cells (NSCs) in mice over the course of several months, researchers identified "short-term NSCs" that quickly differentiate into more specialized neurons, and "long-term NSCs" that continually divide and replicate themselves to maintain an ongoing reserve of stem cells with the ability to generate many different cell types in the brain. This key population of long-term NSCs divided less often and failed to maintain their numbers as the mice aged.

The scientists next examined thousands of genes in the long-term NSCs, which were dividing less often and had slipped into an inactive state known as quiescence. The gene activity of the quiescent NSCs varied greatly in young versus middle-aged animals. As expected, there were changes in genes that control how long-term NSCs divide, as well as generate new neurons and other brain cells. Remarkably, there were many important changes in gene activity related to biological aging at younger ages than anticipated. These pro-aging genes make it more difficult for cells to repair damage to their DNA, regulate their genetic activity, control inflammation, and handle other stresses. Among the pro-aging genes, the scientists were most intrigued by Abl1, which formed the hub of a network of interrelated genes.

Using an existing, FDA-approved chemotherapy drug called Imatinib, scientists could easily inhibit the activity of the gene Abl1. The scientists gave older mice doses of Imatinib for six days. After the drug blocked the activity of the gene Abl1, the NSCs began to divide more and proliferate in the hippocampus, the part of the brain responsible for learning and memory. We've succeeded in getting neural stem cells to divide more without depleting, and that's step one. Step two will be to induce these stem cells to make more neurons. Step three will be to demonstrate that these additional neurons actually improve learning and memory."

All cells maintain a network of cleaning systems that remove and recycle unwanted proteins. One school of thought holds that when the process, called autophagy, malfunctions in neurons, the toxic buildup of proteins can promote neurodegenerative diseases such as Alzheimer's. Now, scientists have shown that a drug designed to invigorate a specialized cellular garbage disposal mechanism ameliorated symptoms in two mouse models of Alzheimer's.

The system the drug targets is called chaperone-mediated autophagy (CMA), in which single proteins are selected and escorted to spherical vesicles in cells called lysosomes, where they are then degraded. Once at the lysosome, the protein-chaperone complex binds to receptors called lysosome-associated membrane protein type 2A (LAMP2A) to trigger the destruction process. The drug, called CA, works by ramping up LAMP2A to boost CMA activity.

CMA activity normally drops as people age, but neurodegenerative disease can make it worse, further affecting the normal protein balance in the brain. The researchers tested whether a CMA activator like CA could protect against Alzheimer's. They gave the oral drug to mice that either had a tau abnormality or a combination of toxic tau and beta-amyloid protein clumps. The drug significantly reduced levels of tau and beta-amyloid, as well as plaques, in the brains of the animals. The treatment also normalized the animals' walking ability and improved visual memory, anxiety- and depression-like behaviors, and neuromuscular strength.

"Previous studies from our lab have shown that the composition of the gut microbiota in animal models of hypertension, such as the SHRSP (spontaneously hypertensive stroke-prone) rat model, is different from that in animals with normal blood pressure. Further, transplanting dysbiotic gut microbiota from a hypertensive animal into a normotensive one results in the recipient developing high blood pressure. This result told us that gut dysbiosis is not just a consequence of hypertension, but is actually involved in causing it. This ground work led to the current study in which we proposed to answer two questions. First, can we manipulate the dysbiotic microbiota to either prevent or relieve hypertension? Second, how are the gut microbes influencing the animal's blood pressure?"

Researchers drew on previous research showing that fasting was both one of the major drivers of the composition of the gut microbiota and a promoter of beneficial cardiovascular effects. Working with the SHRSP model of spontaneous hypertension and normal rats, the researchers set up two groups. One group had SHRSP and normal rats that were fed every other day, while the control group had SHRSP and normal rats with unrestricted food availability. Nine weeks after the experiment began, the researchers observed that, as expected, the rats in the SHRSP control had higher blood pressure than the normal control rats. Interestingly, in the group that fasted every other day, the SHRSP rats had significantly reduced blood pressure when compared with the SHRSP rats that had not fasted.

The researchers transplanted the microbiota of the rats that had either fasted or fed without restrictions into germ-free rats, which have no microbiota of their own. The germ-free rats that received the microbiota of normally fed SHRSP rats had higher blood pressure than the germ-free rats receiving microbiota from normal control rats, just like their corresponding microbiota donors. Additionally, germ-free rats that received microbiota from the fasting SHRSP rats had significantly lower blood pressure than the rats that had received microbiota from SHRSP control rats.

Alzheimer's disease is characterized by the abnormal accumulation and spread of the tau protein in the brain. An international study can now show how tau spreads according to four distinct patterns that lead to different symptoms with different prognoses of the affected individuals. "In contrast to how we have so far interpreted the spread of tau in the brain, these findings indicate that tau pathology in the brain varies according to at least four distinct patterns. This would suggest that Alzheimer's is an even more heterogeneous disease than previously thought. We now have reason to reevaluate the concept of typical Alzheimer's, and in the long run also the methods we use to assess the progression of the disease."

Researchers used a study population of 1,143 individuals who were either cognitively normal or individuals who had developed Alzheimer's in various stages. An algorithm was applied to the data from the tau PET images from the 1,143 individuals, the so-called SuStaIn (Subtype and Staging Inference) algorithm. As expected, many individuals did not show any abnormal tau PET signal, and these were therefore automatically assigned to a tau-negative group. By then cross-validating the tau PET images with a sixth independent cohort, and following up the individuals for about two years, the researchers were able to develop four patterns that best represented the data from the remaining individuals.

"We identified four clear patterns of tau pathology that became distinct over time. The prevalence of the subgroups varied between 18 and 30 percent, which means that all these variants of Alzheimer's are actually quite common and no single one dominates as we previously thought."

Few studies have comprehensively described changes in blood biomarkers of the physiological responses that underlie the sarcopenia reduction that is associated with lifestyle interventions. In this study, we performed secondary analyses of data in a randomized controlled trial of multi-domain lifestyle interventions (6-month duration physical exercise, nutritional enrichment, cognitive training, combination and standard care control) among 246 community-dwelling pre-frail and frail elderly, aged ≥65 years, with and without sarcopenia.

We observed that multi-domain physical, nutritional, and cognitive interventions among pre-frail and frail older adults were associated with favorable changes in sarcopenia and blood biomarkers underlying the muscle mass and physical functional response to intervention. As previously reported, the data are highly consistent with previous studies in showing that physical exercise alone or in combination with cognitive and nutritional intervention was most efficacious in improving muscle mass, lower limb strength, and gait speed. The physical exercise in this study was of moderate and gradually increasing intensity and well tolerated with high adherence rate (85%).

Perhaps unsurprisingly, there was limited effect observed with nutritional intervention delivered with a traditional oral nutrition supplement and not with a formulation with high content of leucine or whey protein or vitamin D, which have been shown in more recent studies to increase muscle mass and muscle function in sarcopenic and malnourished older patients.

Chronic low-grade inflammation associated with oxidative stress is believed to be a major underlying mechanism of aging and aging-related diseases including sarcopenia. Inflammatory markers such as CRP and IL-6 are reported to be associated with decreased muscle mass and strength, and the reduction of inflammation is believed to directly or indirectly ameliorate age-related muscle loss. In the present study, inflammatory levels are observed to be reduced especially by combined intervention, as evidenced by the significant drops in CRP and TNF-α levels. However, the levels of these inflammatory markers were not associated with sarcopenia status or reduction. Thus, the reduction of inflammation may not be the primary underlying mechanism of the response of sarcopenic elderly to lifestyle interventions.

Aged skin is highly associated with loss of function and structural degeneration. With aging, the skin naturally loses its collagen content and elastic fibers become deranged. Additionally, aged skin demonstrates an increase in oxidant activity, and an increase in the production of matrix metalloproteases (MMP), which are typically involved in matrix degradation. Additionally, exposure to UV light is known to promote premature aging of the skin, namely photoaging. Thus, rejuvenation therapies, which focus on the prevention and reversal of skin aging are in high demand in our society, which increasingly aims to maintain a youthful appearance and improve their health.

Adipose derived MSCs (AD-MSCs) have been gaining attention in skin antiaging therapy because of their efficient re-epithelization and secretion of several growth factors necessary for skin regeneration. In recent years, researchers observed histological and structural modifications in aged facial skin after the injection of expanded AD-MSCs, collected from fat removed by liposuction. Treatment with AD-MSCs caused an increase in elastic fibers in the superficial layer of the dermis and modified the collagen and reticular fiber networks, which became more arranged. Subsequently, AD-MSCs were observed to induce complete regeneration of solar elastosis in photoaged skin.

The transplantation of AD-MSCs leads to complete regeneration of dermal elastic matrix components, including oxytalan, elaunin, and elastin fibrillary networks. In solar-aged skin, the normal elastin matrix is usually lost, and AD-MSC-mediated treatment successfully reversed the inhibition of precursor molecules involved in neoelastinogenesis.

Another way to use AD-MSCs in antiaging therapy, in a "cell-free" method of treatment, is by using extracellular vesicles (EVs), which have several advantages over stem cells and their safety issues. Adipose-derived mesenchymal stem cells extracellular vesicles (AD-MSCs-EVs) have anti-photoaging potential and were analyzed as subcutaneous injections in photoaged mice models. The treatment resulted in a decrease in skin wrinkles and promotion of epidermal cell proliferation. Additionally, macrophage infiltration and reactive oxygen species (ROS) production were reduced, which inhibited MMP activation and collagen degradation.