Fight Aging!

A few species such as salamanders and zebrafish can regenerate lost limbs and even large sections of internal organs, provided they survive the injury. In comparison, mammals exhibit far less of a capacity for such proficient regeneration as adults, but the actual limits of regeneration vary widely across mammalian species. Spiny mice can regenerate full thickness skin, cartilage, and muscle as well as lost kidney tissue. The MRL mouse lineage can fully regenerate ear tissue, a capacity that was discovered because many researchers use ear notches to label their mice. Ordinary laboratory mice can regenerate the tips of their digits, and so can developing humans. Most such regenerative capacity for most mammals is lost somewhere between birth and adulthood, however.

The research community is attempting to develop a sufficient understanding of the biochemistry of proficient regeneration in salamanders and zebrafish to be able to provoke such regeneration in mammals. A few genes have so far surfaced as points of investigation, alongside significant differences in the behavior of macrophages and senescent cells in the context of injury and regrowth. In today's open access paper, researchers report on their investigations of the SP transcription factor family, leading to a focus on FGF8, one of the genes for which expression is modulated by SP transcription factors. Suitably guided upregulation of FGF8 expression, which required an enhancer from zebrafish, enhanced the ability of mice to regenerate lost digit tips. This is a modest starting point, and clearly not the whole picture, but years of research are now finally leading to the ability to at least modestly enhance regeneration in mammals.

For regrowing human limbs, this salamander gene could hold the key

Investigating a common gene in three very different species - salamanders, mice, and zebrafish - scientists have discovered the potential for a novel gene therapy aimed at eventually regrowing limbs in humans. In salamanders, SP8 does the work in regenerating limbs. Using CRISPR gene-editing technology, researchers removed SP8 from the axolotl genome. Without SP8, the axolotl could not properly regenerate the limb bones; a similar result occurred with the mouse digits missing SP6 and SP8.

With that information in hand, researchers used a tissue regeneration enhancer found in zebrafish to develop a viral gene therapy. That therapy delivered a secreted molecule called FGF8, a gene that is usually turned on by SP8, to encourage digit bone regrowth and partially restore the regenerative effects of the missing SP genes in mice. Human limbs don't have that kind of regenerative power - but might someday, with a therapy that emulates the abilities of SP genes.

Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors

Instructing regeneration of complex structures in mammals remains an unsolved problem. Gene therapy offers a compelling approach to foster endogenous regeneration by delivering therapeutic gene products to specific cells postinjury. We identified a conserved regeneration-linked epidermal transcriptional program in mouse digit regeneration centered on the SP6 and SP8 transcription factors, involving inflammatory responses from osteoclasts. Spatiotemporally focused expression of FGF8, a known target of SP factors, using a zebrafish-derived tissue regeneration enhancer element via adeno-associated viral vectors, could partially rescue digit tip regeneration in SP knockout mice and accelerate digit regeneration in wild-type mice. Our results demonstrate a contextual gene therapy approach to address limb loss based on genes like SP transcription factors conserved across multiple contexts of appendage regeneration.

Exercise influences the composition of the gut microbiome, which in turn influences capacity for exercise. Thus we see correlations in older people between the composition of the gut microbiome and observed level of physical activity and fitness, but breaking that down into specific contributing mechanisms and their relative importance is a challenge. The fastest path to answers is to alter the gut microbiome composition in defined ways and see how it affects capacity for physical activity. Approaches to alteration are in their infancy; the only approaches robustly demonstrated to produce lasting change are flagellin immunization and fecal microbiota transplantation, but while beneficial in the sense of reversing age-related changes in the composition of the gut microbiome, these approaches do not produce a well defined outcome. The future of this field will likely involve cultivation of defined mixes of hundreds or thousands of species in a synthetic microbiome, a major step up in complexity from the present manufacturing processes for probiotics.

Gut microbiota (GM) plays a crucial role in maintaining health through metabolic, endocrine, and immune functions. With ageing, shifts in GM composition, characterised by increased pathogenic and decreased health-promoting bacteria, contribute to dysbiosis, which is linked to several age-related diseases. Given the global trend of increasing sedentary behaviour (SB) and declining physical activity (PA) among older adults, this study aims to explore the relationships between GM and two critical indicators of healthy ageing, movement behaviours, and physical function.

This cross-sectional study assesses the GM composition, PA levels and physical function of 101 healthy, community-dwelling older adults aged 65-85 years. Participants undertook anthropometric measures and functional tests, wore an accelerometer for 7 days and provided a faecal sample which was analysed using 16s rRNA sequencing. All the results were adjusted for key covariates such as diet, age and activity levels.

Key findings include positive associations of Prevotella copri with moderate-to-vigorous PA, physical function, and negative associations with SB, while Roseburia species were linked to better mobility and strength measures. Conversely, potentially pathogenic taxa like Bilophila wadsworthia and Eggerthella were negatively associated with PA and handgrip strength, underscoring their possible detrimental roles in muscle function and healthy ageing. This cross-sectional study highlights the associations between GM, PA, physical function and healthy ageing in older adults. These findings emphasise the potential for leveraging GM and PA interactions to develop nonpharmacological strategies for promoting healthy ageing, warranting further research through interventional and longitudinal studies.

Link: https://doi.org/10.1155/jare/8981398

Senescent cells accumulate with age, generating disruptive inflammatory signaling that is disruptive to tissue structure and function. Numerous research groups and companies are developing therapies capable of either selectively destroying senescent cells or dampening their signaling. Animal studies and initial human trials suggest that the earliest senolytic treatments used to clear senescent cells, derived from cancer therapies, are safe and effective enough for widespread use. The drugs and compounds used cost relatively little, which is a meaningful argument for greater exploration of their utility. Unfortunately they are not a point of focus outside academia and a small number of anti-aging physicians. Few studies have directly compared first generation senolytic treatments, so the data noted here is interesting for supporting the dasatinib and quercetin combination over navitoclax.

Genetic background is a major determinant of disc degeneration, a leading cause of chronic back pain and disability. Herein, we demonstrate that premature disc cell senescence contributes to early-onset degeneration in SM/J mice and test two systemic senotherapeutic strategies to mitigate it: Navitoclax (Nav.) and a cocktail of Dasatinib and Quercetin (DQ).

While Nav. treatment did not improve severe degeneration in SM/J mice or senescence status, DQ-treated mice showed lower grades of degeneration and a decreased abundance of senescence markers, including p19ARF, p21, and the senescence-associated secretory phenotype (SASP). DQ improved disc cell viability and phenotype retention and retarded fibrosis of the nucleus pulposus tissue. Transcriptomic analysis revealed tissue-specific effects of the treatment, with cell cycle regulation and JNK signaling being commonly affected across different tissue types. A comparison of SM/J data with DQ-mediated aging-dependent amelioration of disc degeneration in C57BL/6 N mice identified Junb and Zfp36l1 signaling as shared DQ targets in the mouse disc.

Notably, the in vitro inhibition studies of the JUN pathway in human degenerated NP cells mimicked the benefits of DQ, namely, a reduction in senescence and SASP. This study reinforces the efficacy of senolytic treatment in ameliorating local senescence and intervertebral disc fibrosis.

Link: https://doi.org/10.1038/s41413-026-00526-4

Chronic kidney disease is largely age-related, though can occur in younger people under some circumstances. It is one of a number of conditions in which research strongly implicates cellular senescence in its onset, progression, and pathology. Senescent cells accumulate in tissues with age. Cells become senescent throughout life, both on reaching the Hayflick limit to replication and in response to stress or damage. A senescent cell ceases replication, grows in size, and generates pro-inflammatory, pro-growth signaling that attracts the immune system and alters the behavior of surrounding cells. In the short term, this signaling is helpful. In youth, senescent cells are cleared efficiently by the immune system, but in later life this clearance falters allowing senescent cells to accumulate in number. Sustained senescent cell signaling contributes to chronic inflammation and disruption of tissue structure and function.

Today's open access paper reviews what is known of cellular senescence in kidney aging versus chronic kidney disease, and notes the arguments for and against considering chronic kidney disease to be a form of accelerated kidney aging. Either way, kidney disease and dysfunction is fairly high on the list of conditions that may be treated earlier rather than later in the development of senotherapeutic drugs that either selectively destroy senescent cells or modulate their behavior to be less harmful. The diabetic form of kidney disease is one of the few conditions for which an initial clinical trial using first generation senolytic drugs has taken place. The similarities between kidney aging and kidney disease might provide hope that low-cost senotherapeutics can meaningfully reduce the burden of dysfunction in older individuals.

Chronic Kidney Disease and Cellular Senescence

As individuals age, kidney function naturally declines, with the decrease in estimated glomular filtration rate (eGFR) starting at around age 30 at a rate of 0.7-0.9 mL/min/1.73 m2 per year in healthy individuals. With age, the kidney undergoes a series of changes that resemble those observed in chronic kidney disease (CKD), including a reduction in the number and size of nephrons, glomerulosclerosis, tubular atrophy, inflammation, dyslipidemia, interstitial fibrosis, and an increase in the prevalence of vascular rarefaction and arteriosclerosis. Furthermore, aging kidneys, similarly to kidneys in CKD, are susceptible to injury, oxidative stress, inflammation, and fibrosis and often struggle to regenerate and recover. However, these changes are typically milder during normal aging than in CKD. Therefore, in many ways, CKD may be likened to a state of premature or accelerated renal aging.

This resemblance partly reflects the unique physiological context of the kidney, where high metabolic activity, chronic exposure to circulating toxins, susceptibility to hypoxia, and limited regenerative capacity of key cell populations amplify stress responses and promote the accumulation of senescent cells. At the cellular level, typical features of premature aging include the accumulation of senescent cells and stem cell exhaustion. Disruption or dysregulation of critical signaling pathways, such as DNA damage, oxidative stress, telomere shortening, loss of Klotho, and oncogene activation, can lead to premature aging. Recent proteomic and transcriptomic studies provide evidence that cellular senescence contributes to CKD progression rather than solely reflecting aging.

CKD patients can be stratified into senescence-based endotypes (sendotypes), where a high-senescence signature dominated by TNF, NF-κB, and MAPK signaling is associated with worse renal function and faster eGFR decline. These senescence-associated pathways were further validated in human CKD biopsies and kidney organoid injury models, confirming their involvement at the tissue level. These findings suggest that CKD is biologically heterogeneous with respect to senescence signaling. The sendotype framework may therefore provide a basis for precision senotherapeutic strategies, where therapies targeting specific inflammatory or senescence pathways (e.g., NF-κB or MAPK signaling) could be applied to patient subgroups most likely to benefit.

The literature highlights cellular senescence as a central mechanism driving both kidney aging and CKD. Nevertheless, determining whether renal senescence serves as a catalyst or an outcome of CKD remains challenging, as current evidence suggests a bidirectional relationship in which kidney injury promotes senescence, while senescent cells further promote inflammation and fibrosis, thereby contributing to disease progression.

A sizable portion of the field of dermatology, arguably the less reputable portion, has long been strongly financially motivated to address the visible signs of aging. In practice, this involved deploying approaches that did not work to any great degree, but were nonetheless popular with patients, one of the many triumphs of marketing over substance that characterize this modern world of ours. The times are changing, however. The advent of a new focus on the mechanisms of aging, coupled with early, narrowly focused rejuvenation therapies that do in fact work to a greater degree than was historically possible, such as the ability to meaningfully reduce the burden of senescent cells in skin, has started a process of transformation in the field. This is a prototype for the transformation that will eventually embrace all medicine for all age-related conditions, a move from coping and marginal therapies to approaches that actually work.

Aesthetic dermatology is undergoing a transformative shift, one that mirrors the broader societal focus on longevity and proactive health optimization. Traditionally, the goals of aesthetic medicine were tied to visible rejuvenation, smoothing wrinkles, restoring volume, and refining contours. Today, patients increasingly seek interventions that not only enhance appearance, but also preserve the vitality, structure, and biological performance of their skin over time.

This shift reflects the evolving science of longevity, which distinguishes between lifespan, the number of years a person lives, and healthspan, the number of years lived in good health, free from disease and functional decline. In dermatology, an analogous concept is emerging, skin healthspan, or skinspan, the duration over which the skin maintains optimal barrier function, immune defense, regenerative capacity, and aesthetic quality.

Cutaneous aging, like systemic aging, is now understood as a modifiable process, shaped by intrinsic genetic programs and extrinsic stressors such as UV exposure, pollution, and inflammation. Advances in epigenetics, cellular senescence research, and regenerative technologies offer an opportunity to shift the focus from late-stage correction to early, proactive biological support. This commentary explores mechanistic pathways underlying skin longevity, including telomeric preservation, epigenetic clocks, senescence reversal via partial reprogramming, and the modulation of mitochondrial function through biomimetic peptides and non-ablative energy-based technologies.

Link: https://doi.org/10.1111/jocd.70788

Cancer is a numbers game; mutations occur at some rate, and some of those mutations result in a cancerous cell. The more cells an individual has, the greater the risk of cancer, all other factors being equal. Of course those factors are not equal. For a physically large species to evolve to become physically large, it must also have evolved superior means of cancer suppression. As researchers explore the biochemistry of large and small mammals, from mice to whales, they are uncovering the mechanisms employed by large species to resist cancer, and which never evolved in smaller species. It is possible that some of these discoveries may lead to ways to prevent or treat cancer in humans, but practical applications resulting from the study of comparative biology remain a future prospect at the present time. Even where specific genes and interactions are identified, it remains unclear as to how best to make use of them in human medicine in a sufficiently safe way to pass muster with the very conservative regulatory bodies.

Across the animal kingdom, cancer risk should, in principle, scale with increasing body size and lifespan. Larger animals contain vastly more cells, and longer lives permit many rounds of cell division, both of which increase the probability of accumulating mutations and undergoing malignant transformation. However, this expectation does not always hold in nature. Some of the largest and longest-lived animals, such as whales and elephants, exhibit a remarkably low cancer incidence.

This incongruency, known as Peto's paradox, suggests that evolutionary pressures have endowed these animals with unusually potent anticancer mechanisms to counteract the mutational burden associated with large bodies and extended lifespans. Indeed, studies in elephants revealed that these large animals have evolved multiple copies of the tumor suppressor TP53 gene, which is associated with an increased apoptotic response that allows the prompt elimination of damaged cells before they become precancerous. Interestingly, sequencing and analysis of several whale genomes, including the bowhead whale - known to live for over 200 years - did not reveal the TP53 duplications seen in elephants, suggesting that whales rely on alternative, previously uncharacterized, anticancer strategies.

In this commentary, we discuss a recent study showing that a key contributor to bowhead whales' exceptional lifespan and cancer resistance is their superior genome maintenance capacity. We further discuss DNA repair as a determinant of longevity in other long-lived species and explore how these naturally occurring mechanisms could be harnessed to improve genome integrity, reduce cancer risk, and promote healthy aging in humans.

Link: https://doi.org/10.1002/1878-0261.70250

Aging is a collection of many varied forms of cell and tissue damage and forms of dysfunction in biological systems that all interact with one another as they progress. A cause can contribute to a consequence that in turn accelerates the cause. Except that in any narrow view there are likely another fifteen contributing causes and various consequences muddying the waters, making it challenging to assign relative importance to any one change or mechanism or interaction. Aging is a big ball of yarn, and there are only so many researchers and so much time. For any given mechanism or interaction, our understanding remains incomplete. Research into aging tends to focus on where the lamp presently shines, on the more well understood and well researched areas of cellular biochemistry and systemic dysfunction, but there is still a great deal that goes on elsewhere.

Today's open access paper is focused on a topic that doesn't come up all that often in the context of research into causes of aging. The authors are interested in the links between age-related changes in metabolism and the onset of frailty, a condition characterized by chronic inflammation, loss of muscle mass and strength, and loss of immune resilience. In the eyes of these researchers, evidence from clinical practice suggests that more attention should be given to metabolic acidosis in older people. This is a failure of metabolism to buffer against acidification of tissue environments. The chain of cause and consequence leading this outcome in aging is far from fully explored, as is the case for near all aspects of aging, but one can trace lines that lead from excessive acidosis to the various contributions to frailty.

Acid-Base Dysregulation Links Aging Metabolism to Frailty

For homeothermic humans, energetic efficiency is built on an optimal internal temperature and optimal pH, both of which are critical for maximizing enzymatic activity. Enzyme function underlies most biochemical reactions, including mitochondrial ATP production, the maintenance of membrane stability, membrane potential, and physiological performance. Overall, pH homeostasis at the intracellular and extracellular levels is preserved through complementary buffer systems and by regulation of cellular metabolism and activity, which are subject to both endocrine and behavioral control. Buffer systems such as the bicarbonate system provide the first line of defense against rapid pH fluctuations. Lungs respond within minutes by changes in ventilation, while the kidneys provide long-term regulation through excreting protons (H+) and generating new bicarbonate.

Accumulating epidemiologic evidence indicates that even "mild" deviations in serum bicarbonates have clinically meaningful implications for aging people. Observational studies have linked serum bicarbonate below 25 mEq/L - a threshold often considered clinically normal - to impaired physical performance, including slower gait speed, reduced muscle strength, and altered gait mechanics. Longitudinal data for initially well-functioning older adults (ages 70-79) further established low serum bicarbonate as an independent predictor of incident, persistent lower-extremity functional limitation. Notably, low bicarbonate level remains a significant risk factor for mortality even in individuals with preserved glomerular filtration rate (GFR > 60 mL/min/1.73 m2). The associations persist even with bicarbonate levels in the low-normal clinical range.

While lower bicarbonate levels are correlated with declining GFR, they also occur frequently in older adults with preserved renal function. In these cases, low bicarbonate plausibly reflects a mild or subclinical metabolic acidosis. The mechanistic association between acidosis and physical decline is thought to involve derangements in skeletal muscle metabolism that promote sarcopenia - the progressive loss of skeletal muscle mass, quality, and strength. These acidosis-induced derangements include catabolic signaling, insulin resistance, increased inflammatory cytokines, mitochondrial dysfunction, and oxidative stress, features that are also reported in the aging-related frailty phenotype. In comparison to aging, this catabolic process occurs more rapidly in chronic kidney disease (CKD) because of not only the greater severity of acidosis but also the accumulation of uremic toxins. Based on in vitro evidence, these toxins inhibit myogenic differentiation and damage mitochondria, further accelerating sarcopenia in CKD.

On this basis, it was proposed that acidosis-induced metabolic derangement in skeletal muscle also represents a key driver in aging-related frailty. However, it is critical to distinguish established mechanism from clinical hypothesis: while the cellular pathways are well-characterized in animal and CKD models, we lack longitudinal human data. Without tracking pH against frailty onset, it remains unclear if acidosis is a driver of frailty, a marker of its presence, or a consequence of muscle wasting (via loss of intracellular buffers).

Some decades ago, the pineal gland was overly mythologized by those interested in intervening in the aging processes, a lot of pseudoscience verging into mysticism. Nonetheless, the pineal gland is important component of the endocrine system, and its functions decline with age. Like the thymus and lymph nodes, the pineal gland becomes structurally disrupted with advancing age, and that is the primary focus of the paper noted here. The researchers seek to categorize this disruption and its relationship with the astrocyte population resident in the pineal gland.

The pineal gland (PG) is an endocrine organ in the brain, primarily composed of pinealocytes (about 95% of the cells); the rest are mainly astrocytes and microglia embedded in a network of blood vessels and nerve fibers. Pinealocytes produce melatonin, which plays an important role in the human body. Numerous studies state changes in the human PG as a result of aging and some neurodegenerative and mental pathologies. A relatively understudied issue is the alteration of the lobular structural organization of the human PG and its potential impact on glandular function.

By analyzing the lobular structure and astrocytic network of the human PG, we have identified two apparently distinct pathways of normal aging. In the first one, an increase in the number of astrocytes within the pineal parenchyma is observed, suggesting a partial compensatory role for astrocytes in maintaining pinealocyte function. In the second pathway, disruption of the lobular architecture appears to result in astrocytic atrophy and a decline in the functional integrity of all pineal components. These observations may explain our findings that the combination of a disrupted lobular structure and a light astrocytic network is the most common pattern, whereas the dense astrocytic network variant is found exclusively in structurally intact lobules of older individuals. Notably, the lobular organization of the pineal gland itself is highly variable and, apart from a slight tendency towards structural disruption with age, does not show a strong age-related pattern.

Another indicator of pineal degeneration is the presence of glial cysts, which are commonly observed in the pineal gland across the examined age range. Although typically asymptomatic, these cysts can significantly reduce the volume of the functional parenchyma. Notably, they are most commonly associated with the above-mentioned combination of a disrupted lobular structure and a light astrocytic network. Based on our findings, we propose that pathological conditions may contribute to structural degeneration of the pineal gland and a subsequent decline in melatonin production; however, normal aging appears to be the primary driver of this process.

Link: https://doi.org/10.3390/ijms27073093

The Gompertz law is a relatively simple equation that describes the exponentially increasing mortality rates observed in an aging population. One fits the equation to existing epidemiological data by adjusting the value of two parameters, α and β. Researchers here use the results of age-slowing interventions in large populations of nematode worms to assign physical, biological meanings to the changes in α and β produced by the treatment of aging. As the researchers describe here, β is related to length of time spent in poor health in later life, while α is related to length of time spent in good health in earlier life.

In populations of many animal species, including humans, mortality rates increase exponentially with advancing age. The scale and rate of increase can be set by two parameters, α and β, respectively, of the Gompertz equation. Interventions that extend lifespan can reduce either or both parameters. A long-standing supposition resulting from use of the equation in human epidemiology is that β corresponds to biological ageing rate, and α to ageing-independent causes of mortality.

Here, we investigate the biological basis of α and β using the nematode Caenorhabditis elegans, through the combined study in populations and individuals of effects of life-extending interventions on mortality and age-changes in health. We demonstrate that reductions in β arise not from slowed biological ageing, but rather from expansion of decrepitude (gerospan) in longer-lived population members. In contrast, reductions in α better reflect healthspan expansion, an indicator of slowed biological ageing. Thus, our investigation presents a new, empirical understanding of the Gompertz parameters that inverts their traditional interpretations.

Link: https://doi.org/10.1038/s41467-026-71780-7

Human life expectancy has increased steadily over time since the 1800s, but much of the analysis is focused on life expectancy at birth, where the dominant effects involve improvements in early life survival. More interesting are the measures of remaining life expectancy at some adult age. These measures also increase over time, but more slowly. In recent decades, the increase in life expectancy at age 65 has increased at a pace that is on the order of one year in every ten. Since this happened over a span of time in which little to no meaningful progress was made in deliberately treating aging as a medical condition, it is reasonable to ask how it happened. As is usual in matters of human epidemiology, firm answers are hard to come by. Correlations are easy to generate, but it is challenging to prove causation, or determine the relative importance of different contributions to an observed outcome.

Nonetheless, researchers have generated insight from the statistics of human mortality. For example work from fifteen years ago shows an equal split between (a) reduced premature mortality, compressing mortality to a smaller range of later ages, and (b) a reduction in mortality in those later ages. It is an open question as to whether these are both manifestations of the same underlying mechanisms, resulting from improvements in public health, reduced exposure to severe infection, general advances in medicine, and so forth. If we accumulate less damage along the way, do we also tend to live longer? Reliability theory suggests this is the case, building on what is known of the statistics of the failure of complex arrays of redundant parts.

In one sense a reduced mortality due to intrinsic causes and age-related disease is equivalent to a slower pace of aging, as aging is defined by its effects on mortality. In another sense, whether aging has been slowed depends on how one defines aging - at the level of mechanisms, capacity, and cellular biology rather than at the level of epidemiology and mortality, that is. Today's open access paper is a consideration of whether we can or should say that increased life expectancy means that aging is slowed versus postponed, and that is a distinction that really does force one to engage with how exactly aging is defined. What, mechanistically, is aging, exactly, if the pace of aging does not change, but the age of onset of aging can vary? This is a very different view to that provided by reliability theory.

The rhythm of aging: Stability and drift in the individual rate of senescence

Human aging is marked by a steady rise in the risk of dying with age - a process demographers call senescence. Over the past century, life expectancy has risen dramatically, but is this because we are aging slower, or simply starting it later? This has been framed as a testable hypothesis: the rate at which the risk of dying increases with age for humans may be a basic biological constant that is very similar and perhaps invariant across individuals and over time. From this perspective, gains in life expectancy would reflect delayed aging, not a change in the underlying process of senescence. But if the rate of aging is truly changing, it would suggest that the biological processes underlying senescence are more responsive to environmental, behavioral, or historical conditions than previously assumed.

We focus on actuarial senescence - the age-related rise in mortality risk - which, in most adult populations, shows an exponential increase in mortality with age, well described by the Gompertz law. The Gompertz slope measures how quickly risk accelerates as deterioration accumulates. Though not a direct biological measure, is widely used as a proxy for the rate of aging. Empirical tests of this hypothesis have yielded mixed findings. This may suggest that the variations in could be historically driven. Period events - such as wars, pandemics, and economic crises - strike multiple cohorts at once, just at different ages, and their lasting consequences can subtly distort the mortality patterns within each exposed cohort through cumulative shifts. As a consequence, when we estimate cohort by cohort, we may be tracing not a pure signal of the aging process, but the lasting effects of these shared historical events. As these shocks accumulate over time, they can produce variations that mimic a change in the slope of mortality, even if the underlying biological rate is constant.

We ask whether cohort-to-cohort variation in the Gompertz slope reflects a shift in the pace of aging or the effects of period shocks. We test this idea using a framework that decomposes the pace of senescence into three components: a biological baseline, a long-term trend, and the cumulative impact of period shocks. Applying this to cohort mortality data above age 80 from 12 countries, we find that once period shocks are accounted for, there is no statistical evidence of a long-term trend, consistent with the hypothesis. Analyses using lower starting ages yield the same qualitative conclusion. Rather than indicating a change in the process that drives senescence, these variations are consistent with echoes of shared historical events. Together, these findings indicate no evidence of a persistent directional change in the individual rate of aging.

This stability does not imply that aging is fixed in all aspects. Over the past century, survival has shifted toward older ages and life expectancy has increased substantially. These improvements may primarily reflect declines in baseline and background mortality rather than persistent changes in the rate at which mortality rises with age. In demographic terms, the onset of senescence may be postponed even if its tempo remains stable.

The aging and longevity of flies is very dependent on intestinal function. The noted longevity-associated gene INDY acts on intestinal function, for example. Here, researchers report on their investigation of the role of the gut microbiome in INDY-related longevity in flies. As might be expected given the present state of knowledge of the role of the gut microbe in long-term health and aging, there are signs of a contribution. These results are only a first step, however; the gut microbiome is a complex array of different microbial species, and there is a great deal more that might be catalogued in terms of its relationship to genetic associations with longevity in this species.

Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear.

Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiome was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiome and Indy. Indy down-regulation was linked to reduced expression of the JAK/STAT signaling ligands Upd3 and Upd2 in the midgut of young flies, which likely contributes to preserved intestinal stem cell homeostasis. Altogether, our results suggest that Indy reduction impacts microbiome load and composition, which preserves gut homeostasis and extends lifespan through impacts on JAK/STAT signaling pathway.

Link: https://doi.org/10.64898/2026.03.25.714291

PEPITEM is a circulating peptide involved in resolution of inflammation and reduction of chronic inflammation. Levels of PEPITEM decline with age, which is one of the reasons why inflammatory athritis becomes worse with age, in that this inhibitory mechanism declines in effectiveness. Studies in animal models have shown that injection of synthetic PEPITEM can improve symptoms; an example of this sort of work is noted here.

Inflammatory arthritis is a group of diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), where the immune system attacks the joints, causing severe joint damage, pain, and disability. Under normal conditions, adiponectin in the bloodstream stimulates white blood cells to produce PEPITEM, which in turn reduces white blood cell migration in the tissues, preventing an unregulated inflammatory response. However, in inflammatory arthritis, white blood cells fail to respond to adiponectin, and secrete less PEPITEM in the joint. The natural 'break' that prevents white cell migration into the joint cavity is lost, and the inflammatory response becomes unregulated.

The initial study of peripheral blood mononuclear cells (PBMCs, white blood cells) harvested from treatment-naïve human donors with suspected inflammatory arthritis showed a reduced capacity to respond to adiponectin, which could be restored by the addition of PEPITEM. Further examination of whole blood indicated a lower bioavailability of PEPITEM in patients with early RA, leading the researchers to hypothesise that supplementation with PEPITEM could restore immune regulation and reduce the inflammatory changes seen in early-stage disease.

Their work in mouse models of inflammatory arthritis and gouty arthritis showed that injection of synthetic PEPITEM could prevent the onset of inflammatory arthritis, with significant reductions in disease incidence. In addition, joint swelling was reduced by PEPITEM when compared with infliximab - the current standard of care. Tissue studies confirmed that these changes were mirrored in synovial tissue (tissue inside the joints), with significantly less joint inflammation, cartilage damage, and bone erosion observed in PEPITEM treated mice, and significantly fewer white blood cells infiltrating the joints. Molecular studies showed significant down regulation of inflammatory mediators (NF-kB and COX2 protein) within the synovial tissue in PEPITEM-treated mice compared to controls, and a significant increase in the foxp3 transcript, which is crucial for the development of a type of white blood cell that suppresses the immune response, to prevent excessive inflammation and autoimmune disease.

Link: https://www.birmingham.ac.uk/news/2026/pepitem-replacement-therapy-shows-potential-for-early-stage-inflammatory-arthritis

The World Health Organization (WHO) launched intrinsic capacity into the space of ideas relating to the study of aging a decade ago; it is defined as "the composite of all the physical and mental capacities that an individual can draw on." At a more detailed level, intrinsic capacity is envisaged as the sum of motor capacity, sensory capacity, general vitality, psychological wellness, and cognition capacity. What the WHO authors did not specify is how to measure any of this, specifically and in detail.

Putting a fuzzy definition in front of the scientific community is like dangling catnip in front of a bunch of cats, and so now there exist a fair number of proposed approaches for measuring intrinsic capacity that are accompanied by published epidemiological data, but there is little to no consensus as to which of these approaches is the one to move ahead with, and no great ability to compare the data produced via one scientist's intrinsic capacity to data produced via another scientist's intrinsic capacity.

This hasn't stopped a continued flow of new publications in which researchers compare someone's definition of intrinsic capacity to other health data, such as epigenetic age. This may all settle into a consensus at some point, but postponing anything to await that outcome seems unwise. Free-form debates of this nature can last decades. Today's open access paper is another that seeks to build upon the concept of intrinsic capacity and efforts to define it precisely, this time in the direction of animal models of aging. Given that no-one can agree on how intrinsic capacity should be measured in human patients, why not expand that discussion to the animal models that inform the development of new therapies with the potential to slow or reverse aspects of aging?

Could animal models be used to longitudinally track intrinsic capacity during aging?

The World Health Organization (WHO) recently highlighted the importance of promoting healthy aging worldwide, a process characterized by the maximization of functional ability, enabling well-being in older adulthood. This concept inspired the development of the Integrated Care for Older People (ICOPE) program and the Intrinsic Capacity (IC) construct, with the latter serving as core element of ICOPE for clinical use. IC represents the composite of all mental and physical internal attributes of an individual. It is often operationalized through five key domains: cognition, locomotion, vitality, sensory function, and psychological capacity.

Research on IC during aging in humans is growing, being marked by high IC variability. Longitudinal monitoring must be prioritized to capture aging trajectories and identify modifiable risk factors. However, the need for a long-time window spanning decades of human life poses a significant challenge to investigating IC decline over time. In contrast, animal models offer a strategic alternative due to their shorter lifespans compared to humans. For example, the typical lifespan of a mouse is 2-3 years, whereas specific fish models (e.g., killifish) may live only 4-6 months. Thus, leveraging these models for longitudinal IC tracking offers a viable pathway that may expedite the elucidation of IC dynamics and mechanisms during aging.

Preserved functional ability can be objectively assessed through behavioral paradigms in animal studies. By using these measurements in observational or experimental settings, animal models can recapitulate the longitudinal trajectories of IC during aging. To facilitate crosstalk with humans and accurately capture age-related changes in IC, assessment tools should meet specific criteria: they should target the corresponding IC domains in humans, show a decline over time with aging, and exhibit sufficient amplitude to distinguish meaningful functional loss. Here, we discuss how longitudinal IC investigations in mice and fish may advance human research and care during aging. Particular attention will be given to assessing, in experimental models, all IC domains longitudinally, interactions across IC domains, and the definition of a set of potentially informative IC assessments in both mice and fish.

In the search for ways to slow the age-related loss of muscle mass that afflicts every older person, researchers here find that ATF5 is a point of control that regulates a trade-off between muscle mass and muscle quality. Mice lacking functional ATF5 retain muscle mass with age, but muscle quality declines to a greater degree instead. This rules it out as a target for therapy. It is always possible that further investigation of the interactions surrounding ATF5 will lead to insight into how to decouple mass versus quality, but that sort of investigation of biochemical pathways tends to take a very long time.

In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging.

To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body knockout (KO) and wild-type (WT) male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial reactive oxygen species production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of mitochondrial protease LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance.

Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Link: https://doi.org/10.18632/aging.206365

Enormous costs are imposed by regulators in the US and Europe on the process of manufacturing a candidate drug to Good Manufacturing Practice (GMP) standards and then running a first clinical trial. Combine this with three years of a bad market for biotech, in which investors have pulled back from investing in preclinical companies, and one sees a much greater pressure than usual to expand alternative paths to obtaining initial human data in a responsible way. Right to Try initiatives within the US are underway, and ever more groups within the medical tourism industry are attempting to position themselves as service providers for an alternative to a first clinical trial in the US or Europe. Próspera in Honduras is the most visible of a fair number of entities. At the end of the day, much of the cost and requirements imposed by the FDA and other bodies are not necessary for responsible safety. When regulators make the task of conducting manufacture and a safety trial in humans cost $20M, but it can actually be accomplished responsibly for $5M, as is the case for many classes of therapy, something must change - and change is coming.

Mitrix Bio has reported preliminary Phase 1 safety results for what it describes as large infusions of transplanted mitochondria in humans, while simultaneously launching a small network of clinics offering the experimental intervention under Right to Try frameworks. Taken together, the announcements mark a transition from laboratory concept to early clinical deployment - albeit on a limited scale.

The initial safety work was conducted at a clinic in Dallas, Texas, involving two older participants who received escalating doses of transplanted mitochondria, with monitoring of blood chemistry and physical condition throughout. According to the company, no obvious adverse effects were observed during the study period. Alongside this, new Mitochondrial Transplant Institute clinics have opened in Newport Beach, Dallas and Palm Beach, where treatments will be offered on an individualized basis by physicians, targeting a wide range of chronic and degenerative conditions.

Mitrix's approach involves the use of bioreactors to grow mitochondria derived from an individual's own cells, with the aim of enabling larger-scale infusions. In the recent safety study, doses were increased incrementally, allowing investigators to assess tolerability before proceeding further. The absence of immediate adverse effects supports continued investigation, and though efficacy data has not yet been released, the company is aiming for full efficacy data by the end of this year.

Link: https://longevity.technology/news/mitrix-moves-mitochondria-into-the-clinic/