Fight Aging!

A great deal of advocacy for the development of therapies to slow and reverse aging has moved on from a focus on reducing suffering. That the majority of the arguments now focus on economic productivity and reduced entitlement costs reflects a broad and possibly quite correct cynicism about what motivates the politicians, wealthy political influencers, and bureaucrats who collectively control the largest flows of funding and support in our societies. Private funding for research and development focused on longevity remains very motivated by the potential reduced suffering, and indeed the potential to reduce one's own personal suffering in the years ahead. However, the longevity industry of the recent past, and for the near future, exists in a state of tension as it attempts to make the transition from a privately supported new venture to an established field supported by the full panoply of state controlled medical systems - to be as openly and comprehensively backed by governments as cancer research and development.

Most advocates these days appear to believe that the way to make this happen is to exploit the high level of anxiety in the ruling classes of much of the world that centers around the demographic transition to ever increasing numbers of older people, and the costs of old age. The governments of the world have largely chosen to exert a great deal of control over the development and provision of medicine, to the point of it becoming an expense for them, a burden much akin to the mess that was made of pension entitlements, the creation of large enough promises of future expenditure to financially ruin the systems created to manage them. Treatments for aging are a deus ex machina that will save the system, or that is the hope being pushed into government circles by advocates attempting to achieve greater support for the development of longevity therapeutics. The realpolitik always seems somewhat shabby in full daylight when it departs utterly from the considerations of what aging does to an individual, physically and mentally. The true reason to build therapies to treat aging is because this offers the strong possibility of a very sizable reduction in human suffering and death, not because it can prop up dysfunction systems of governance.

The longevity dividend: Why governments and markets must catch up

'How much' often matters less than 'how fast'. Financial systems might comfortably accommodate a decade increase in life expectancy if it emerges gradually over half a century, but could they accommodate the same increase within 5 years? Economies are built to absorb gradual change and are much less comfortable with discontinuities. Human longevity may be approaching that kind of discontinuity. The latest scientific advances point to the emergence of what we have termed 'system-level' therapeutics capable of bringing about rapid, non-linear changes in both healthspan and lifespan trajectories, challenging the incremental paradigms that underpin current economic and demographic forecasting models. If they do, governments, healthcare systems, insurers and pension funds will have to respond to a break with history, not a continuation of it.

Public debate often treats longevity as a cost curve. That is only half the ledger. In an era of demographic ageing and stagnant economic growth forecasts, one overlooked truth is emerging: longevity science may be the most powerful economic productivity lever of all time. Governments spend billions annually on education, digital transformation and industrial innovation - all in the name of boosting national productivity. Yet few acknowledge that the single largest drag on workforce participation is declining health in midlife and beyond due to ageing. In the United States, the direct costs of chronic health conditions total around $1.1 trillion - equivalent to 5.8% of US gross domestic product (GDP). When indirect costs of lost economic productivity are included, the total costs of chronic diseases in the United States increase to $3.7 trillion - in other words, they equate to almost 20% of the US GDP.

The economic argument for longevity research is clear: targeting the root causes of ageing is not just a healthcare imperative, it is set to become a non-negotiable economic strategy. Governments should treat it as such, allocating funding accordingly and incentivising translational research, clinical trials, and public-private partnerships in this field. In the 20th century, public investment in antibiotics and vaccines changed the world. In the 21st century, ageing biology has the potential to do the same.

Sarcopenia is the name given to severe age-related loss of muscle mass and strength. This loss occurs steadily throughout later life. The present state of research into this condition is representative of aging more generally, in that while a range of quite different mechanisms all have strong supporting evidence for a meaningful contribution to sarcopenia, their relative importance to one another is unclear, how they connect to one another at the detail level is unclear, which are largely causes and which are largely consequences of one another, and their relationship to the known underlying forms of cell and tissue damage that drive aging is unclear. See the evidence for loss of muscle stem cell function to be the primary cause of sarcopenia, and surrounding discussions on that topic, for example. Here, researchers point instead to disruption of lactate metabolism in both liver and muscle tissue as the primary cause of sarcopenia; the involvement of the liver a reminder that no one tissue stands alone in the matter of aging. All organs communicate with one another and are interdependent in many different ways.

Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle.

Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1α improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1α in the liver as a pharmacological target for sarcopenia.

Link: https://doi.org/10.1126/sciadv.aeb4011

Normal cell metabolism, particularly the activities of mitochondria, generates oxidizing molecules that react with proteins to disrupt their function. This damage occurs constantly, and is repaired constantly. Cells remove damaged proteins, undo oxidative changes, and make use of antioxidant enzymes such as SOD1 to prevent damage from occurring in the first place. With age, oxidation increases and becomes an important component of cell dysfunction. Here, researchers note that SOD1 itself can become oxidized and harmful, and discuss the importance of antioxidants disabled by oxidization in the growth of age-related oxidative stress in cells. The specific focus is on skin aging, but the points have relevance to all tissues.

As the body's primary barrier against environmental insults, the skin is continually exposed to oxidative stress, which may contribute to progressive proteotoxic stress. Excess reactive oxygen species (ROS) can overwhelm cellular protein-quality-control systems, promoting the accumulation of damaged and misfolded proteins, proteome instability, and eventual protein homeostasis (proteostasis) collapse. Superoxide dismutase 1 (SOD1), a Cu/Zn-dependent cytosolic antioxidant enzyme and key component of cellular defense against superoxide radicals, is itself vulnerable to oxidative modification. ROS-mediated post-translational oxidation of SOD1 may promote its misfolding and the formation of toxic protein species, potentially establishing a self-amplifying cycle of superoxide accumulation, further protein damage, and impaired cellular homeostasis.

In cutaneous cell types, including dermal fibroblasts and epidermal cells, these processes may be especially relevant to age-associated declines in proteostatic capacity and skin aging. This review distinguishes established skin-specific evidence from hypotheses extrapolated from other systems and synthesizes current evidence on the interplay among ROS-induced protein damage, proteostasis failure, SOD1 dysfunction, and cutaneous aging. We highlight the bidirectional relationship between proteostasis collapse and mitochondrial dysfunction, which may establish a self-reinforcing cycle of oxidative stress, cellular senescence, and chronic low-grade inflammation. These interconnected processes may converge to promote extracellular-matrix remodeling and tissue dysfunction, contributing to wrinkles, reduced elasticity, and impaired barrier function.

Link: https://doi.org/10.1016/j.arr.2026.103351

A few species of hydra are immortal in their normal environmental conditions, meaning that function does not decline over time and mortality risk does not increase over time. Researchers spent a good deal of time taking care of hundreds of hydra some years ago to demonstrate that this is the case. Hydra are lower animals, essentially a bundle of stem cells capable of regenerating and replacing any part of their bodies, somewhat analogous to an ambulatory embryo. It is an open question as to whether anything we can learn from their biochemistry can be useful in human medicine.

In today's open access paper, researchers report on the employment of telomerase by hydra. Telomeres are repeated sequences at the end of chromosomes that shorten with each cell replication, creating a clock that leads to cell death when telomeres are too short. In most species, somatic cells are limited in this way in order to minimize the risk of cancer, while stem cells employ telomerase to maintain long telomeres while delivering a supply of new daughter somatic cells to replace losses. The body is just a temporary vehicle for an immortal population of germline stem cells, in one view. Hydra are obvious very different in terms of the balance between stem cell behavior versus somatic cell behavior in individuals.

Telomerase expression and activity in the immortal cnidarian Hydra

Most living eumetazoan animals are mortal. A fundamental mechanism underlying cellular and organismal aging in many species is the progressive shortening of telomeres - protective nucleoprotein structures at chromosome ends. The finite replicative lifespan of somatic cells is linked to telomere attrition. The discovery of telomerase, a ribonucleoprotein complex with reverse transcriptase activity that synthesizes telomeric repeats, provided a molecular explanation for the unlimited proliferative potential of germlines, stem cells, and most cancer cells. In humans, telomerase is not expressed in most somatic tissues and is active primarily in germ cells, stem cells, and certain rapidly renewing tissues such as blood or intestinal epithelium.

Comparative studies indicate that telomere dynamics correlate with lifespan, with slower shortening rates in long-lived species. Recent cross-species analyses, however, reveal a more complex picture, suggesting that the relationship between telomere maintenance strategies (telomerase activity vs. alternative lengthening) and longevity is not strictly deterministic. Nevertheless, it remains a prevailing hypothesis that biologically immortal organisms must possess robust mechanisms for telomere maintenance. Supporting this, sustained telomerase activity in somatic tissues has been documented in non-senescent invertebrate models such as planarians and long-lived bivalves.

Importantly, several taxa, including some hydras, planarians, and rotifers, have been reported to exhibit negligible or undetectable senescence. In this study, we characterized the telomerase of Hydra vulgaris. The expression pattern of the telomerase catalytic subunit (hyTERT) mRNA correlates with regions exhibiting high proliferative potential and remains unchanged during budding or regeneration. These findings were further corroborated by measurements of telomerase activity. Our data suggest that telomerase may play a role in the immortality of Hydra.

Persistent infections such as cytomegalovirus and other herpesviruses most likely accelerate aging, primarily via harmful effects on the immune system that lead to earlier immunosenescence and chronic inflammation than would otherwise be the case. A range of mechanistic and epidemiological research broadly supports this hypothesis. It remains challenging to completely clear persistent viral infections, however. If a strong antiviral therapy existed, epidemiological data would likely prove the point one way or another within five to ten years, as effects on aging would become apparent in older populations. As it stands, the present relatively weak antiviral therapies show some evidence for positive effects on late life risk of mortality and age-related disease, but not in all studies.

Asymptomatic infections are traditionally considered harmless, reflecting effective immune control and the absence of clinical disease. Yet growing evidence shows that these silent encounters with microbes are far from being immunologically neutral. Throughout life, humans are challenged by a remarkably broad spectrum of viruses and bacteria, including latent pathogens that persist, fluctuate, or periodically reactivate without producing significant symptoms. From an evolutionary standpoint, this represents a fundamental trade-off. Long-lived hosts benefit from maintaining diverse commensal, latent, and low-grade persistent microbes that enhance immune readiness, promote cross-protective immunity, and reduce vulnerability to severe infections. However, this adaptive advantage is counterbalanced by the continuous burden of chronic, almost undetectable immune activation and inflammation, and by the energetic cost of sustaining such mechanisms of surveillance.

In this regard, retroviral integrations provide a striking illustration of how persistent viral presence has shaped the evolution of complex organisms by introducing new regulatory elements, immune modulators, and developmental programs. These ancient viral imprints demonstrate that clinically-silent host-microbe interactions can exert long-term selective pressures and influence species-specific biological trajectories. At the individual level, repeated asymptomatic infections trigger transient waves of immune activation, endothelial perturbation, mitochondrial stress, and complement engagement. Although each episode is mild and self-limited, their cumulative burden generates micro-damage that accelerates immunosenescence, perturbs metabolic and vascular homeostasis, and contributes to the progressive rise in systemic inflammation characteristic of aging.

Link: https://doi.org/10.1016/j.arr.2026.103340

Cells become senescent constantly throughout life in response to various forms of damage and stress, ceasing replication and generating a potent mix of inflammatory signals. In youth, these cells are promptly cleared by the immune system, but with advancing age they begin to linger and accumulate. The inflammatory signaling becomes disruptive to tissue structure and function when sustained over the long term, and this is an important contribution to degenerative aging. Here, researchers show that macrophage cells in the kidney express increasing amounts of the P2RX7 receptor on the cell surface as they progress towards becoming senescent, and blocking this receptor with a suitable antagonist small molecule reduces macrophage senescence and improves kidney function.

Macrophage senescence is a pathological feature in aging or diseased kidneys. However, the role of senescent macrophages in kidney injury and aging has not been fully elucidated yet. We integrated the analysis of single-cell RNA sequencing datasets and the adoptively transfusion of pretreated bone marrow-derived macrophages to investigate the role of renal macrophage senescence in kidney injury. Here, we portrayed the senescence trajectory along multiple time points in infiltrating macrophages, and observed the persistent increase of macrophage-expressed purinergic receptor P2RX7 along the senescence trajectory in injured kidneys of septic mice.

Importantly, our discovered small-molecule P2RX7 antagonist strikingly improved kidney function and pathological damage, as well as mitigated macrophage senescence in septic and aging mice. Mechanistically, P2RX7 antagonist could promote the wound healing, migration, and proliferation capacity of senescent reparative macrophages, thus exerting anti-inflammatory effects and repairing kidney tissues. Together, our findings illustrate the crucial participation of senescent macrophages in septic kidney injury, and offer novel therapeutic strategy via intervening P2RX7 against immunosenescence-associated kidney injury and aging.

Link: https://doi.org/10.7150/ijbs.138299

Despite considerable and growing effort put towards the development of novel means to slow and reverse aging over the past thirty years, the longest lived laboratory mice remain those lineages first established in the 1990s with mutations that disable growth hormone metabolism, such as via knockout of growth hormone or growth hormone receptor genes. These mice are small and vulnerable to cold, but live as much as 70% longer than their unmodified peers.

It seems likely that this has little relevance to human aging, as Laron syndrome is the analogous human inherited condition, usually caused by a growth hormone receptor loss of function mutation. Laron syndrome patients may have a lower incidence of some age-related conditions, but do not appear to live meaningfully longer than the rest of the human population. One of the most important lessons of the past thirty years of study of calorie restriction and growth hormone metabolism in the context of aging is that these interventions produce much larger effects in short-lived species than in long-lived species.

Nonetheless, disruption of growth hormone metabolism remains an active area of study. You might recall a paper published five years ago or so in which researchers showed that disruption of growth hormone metabolism starting in adult life, at six months of age in mice, still produced a slowing of aging. Here, the same team repeats the same effort starting at twelve months of age, mid-life for mice. The size of effect on life span is much the same in male mice when starting at this later age, but worse in female mice. In either case, the extension of life span is modest in comparison to life-long disruption of growth hormone metabolism, less than 10%. Like the existence of Laron syndrome, this argues against putting meaningful effort into attempts to build human therapies based on this mechanism.

Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution

Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model.

This midlife Ghr disruption produced the expected endocrine signature of GH resistance, including reduced circulating IGF-1 and elevated GH levels. Importantly, lifespan was significantly extended in both sexes without major effects on somatic growth. Despite increased adiposity, male 12mGHRKO mice exhibited improved insulin sensitivity and protection against age-related deterioration of neuromuscular performance and bone microarchitecture. Single-nucleus RNA sequencing (snRNA-seq) of liver tissue identified a reduction of B-cells in both sexes and a dimorphic transcriptional remodeling, including a shift toward feminized gene expression in male hepatocytes, marked by reduced male-biased gene expression and increased female-biased transcriptional programs, consistent with impaired pulsatile GH-STAT5 signaling.

Together, these findings demonstrate that suppression of GH signaling initiated in middle age is sufficient to reshape hepatic transcriptional programs and promote healthy longevity, supporting the GH/IGF-1 axis as a promising target for gerotherapeutic interventions.

Researchers here run a much larger than usual mouse study to show a ~10% slowing of aging, depending on how one slices the data, in mice genetically engineered to exhibit a growth hormone mutation that changes the interaction of circulating growth hormone with the growth hormone receptor on cell surfaces. Growth hormone is switched from a receptor agonist (binds with and activates the receptor) to a receptor antagonist (binds with the receptor without activating it, blocking other molecules from activating it). This extension of life is entirely expected given all of the long-lived mouse lineages in which growth hormone metabolism is in some way sabotaged. This specific form of sabotage had not been tested rigorously, however. While interesting, it is worth noting that humans with Laron syndrome, an inherited dysfunction of growth hormone metabolism analogous to many of the mouse models exhibiting longevity, do not appear to live meaningfully longer than the rest of the human population.

Interventions that disrupt growth hormone (GH) action are recognized as some of the most potent methods for extending lifespan. Accordingly, GH receptor antagonists (GHA) represent potential therapeutics to improve healthspan. Somavert (Pegvisomant for injection), used for treating patients with acromegaly, is currently the only FDA approved GHA. This drug was based on our laboratory's early 1990s discovery that mutating a codon for a conserved glycine - at position 119 in bovine GH or 120 in human GH - to a variety of amino acids, including lysine, ultimately converted GH from an agonist to antagonist. Since Pegvisomant has poor affinity to rodent GHR, it has not been tested for its ability to extend lifespan in rodents.

To address this gap, we evaluated survival in GHA transgenic mice, a mouse line that played a crucial role in the discovery and development of Pegvisomant and has been maintained in our lab since 1991. While a prior study with several limitations failed to detect lifespan extension in GHA mice, our current study addressing these limitations shows that both median and maximal lifespan were significantly increased in male and female GHA mice, with maximal lifespan extended by 186 and 265 days, respectively. Analysis of an independent cohort of 2-year-old mice revealed that GHA males and females were less frail with enhanced grip strength despite increased adiposity. These findings demonstrate for the first time that GH antagonism can improve health and extend lifespan.

Link: https://doi.org/10.1111/acel.70697

Researchers have been working towards practical approaches to inhibiting RUNX2 activity as a way to slow age-related loss of bone mineral density. Bone extracellular matrix is constantly remodeled throughout life, created by osteoblast cells and destroyed by osteoclast cells. In youth these activities are balanced, but with advancing age osteoclast activity comes to dominate. Many drugs have been deployed in attempts to improve osteoblast activity or suppress osteoclast activity, but researchers continue to try to create incrementally better approaches. RUNX2 inhibition acts by increasing osteoblast activity. Here, a novel RUNX2 inhibitor emerging from the cancer research community is demonstrated to slow loss of bone mineral density in mice.

Osteoporosis is a metabolic bone disorder characterised by low bone mass, structural deterioration, and increased fracture risk. Current therapies are limited. Antiresorptives such as bisphosphonates and denosumab reduce fracture risk but long-term use carries risks of atypical femoral fractures and osteonecrosis of the jaw. Anabolic agents, including parathyroid hormone (PTH) derivatives and analogues, namely teriparatide and abaloparatide, are effective but require daily injection. Romosozumab offers monthly dosing but has cardiovascular safety concerns. Hormone replacement therapy also reduces fracture risk but its association with breast, ovarian, and uterine cancer risk limits patient uptake. Thus, new treatments with few side effects and broader applicability remain a clinical priority.

We recently evaluated the small molecule RUNX2 antagonist CADD522 in several preclinical cancer models. RUNX2 is critical for in utero skeletogenesis and cancer metastasis. Unexpectedly, CADD522 reduced cancer-induced bone disease, suggesting potential utility in osteoporosis. Here, we investigated whether RUNX2 inhibition could protect against post-menopausal bone loss. In an ovariectomy-induced mouse model, CADD522 (25 mg/kg, three times weekly for eight weeks) enhanced bone formation, preserved trabecular microarchitecture and reduced marrow and peripheral adiposity. Cross-species pharmacokinetic and toxicological studies demonstrated oral bioavailability, favourable short-term tolerability, and target engagement despite rapid systemic clearance, while cellular thermal shift assays confirmed direct engagement of RUNX2.

Together, these findings identify RUNX2 inhibition as a therapeutic strategy that simultaneously improves skeletal integrity and metabolic homeostasis, supporting further development of CADD522 for osteoporosis and other RUNX2-driven diseases.

Link: https://doi.org/10.1038/s44386-026-00076-z

The immune systems of the body and brain are distinct and separate, or at least largely separate, influencing one another via signaling. The blood-brain barrier keeps the vast majority of immune cells in the body out of the brain, and vice versa. A few channels have been discovered in recent years whereby a small number of adaptive immune cells, such as T cells, enter the brain in the normal course of events. Additionally, the blood-brain barrier becomes dysfunctional and leaky with age, allowing a wide range of unwanted cells into the brain, T cells included.

Increasing inflammatory activity in the innate immune cells of the brain known as microglia is a growing focus of research interest in the context of aging and neurodegenerative conditions. While some of of this maladaptive behavior arises from reactions to local conditions and internal age-related damage, some is driven by interactions with the body's immune system. Along the way, attention has also turned to the entry of T cells into the brain, and their potential role in provoking inflammatory neurodegeneration. In today's open access paper, for example, researchers demonstrate that dendritic cells encourage T cells to enter the brain to cause problems. Removing the dendritic cells in mice reduces the impact of T cells on the aging of the brain and progression of neurodegeneration.

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration

Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease and certain forms of frontotemporal dementia, defined by the intracellular aggregation of hyperphosphorylated tau protein, which tightly correlates with neuronal dysfunction and death. Tauopathy is accompanied by increased reactive microglia and astrocytes and increased T cells in the brain, particularly CD8+ cytotoxic T lymphocytes. We previously found that depleting T cells significantly ameliorated tau-mediated neurodegeneration in p.Pro301Ser (P301S) tau transgenic mice expressing human APOE4 (TE4), supporting an active role for T cells in driving tau-mediated neurodegeneration.

Clonally expanded CD8+ T cells constituted a majority of the infiltrating CD3+ T cells (~60-70%) in TE4 brain. Conventional type 1 dendritic cell (cDC1s) are specialized antigen-presenting cells (APCs) that perform antigen cross-presentation, a process that involves presenting exogenously derived antigens on major histocompatibility complex class I (MHC-I) molecules to prime CD8+ T cells. During T cell priming, naive CD8+ T cells receive antigenic, co-stimulatory and cytokine signals from APCs, driving their differentiation into effector cells that subsequently migrate to peripheral tissues to execute their immune functions.

Here, we investigated the role of cDC1s in tau-mediated neurodegeneration by genetically ablating cDC1s or disrupting their antigen cross-presentation capacity in TE4 mice. Both interventions markedly protected against neurodegeneration and selectively reduced CD8+ T cell accumulation in the brain. Importantly, we found that cDC1-dependent antigen cross-presentation of a brain-derived antigen occurs outside central nervous system tissues, highlighting peripheral antigen presentation as a potential therapeutic target for tauopathies, including Alzheimer's disease.

Atherosclerosis is the largest cause of human mortality, producing stroke and heart attack when fatty plaques obstructing arteries rupture. There is accordingly a great deal of research aimed at influencing the course of the condition. Reversal of plaque growth to clear arteries and remove potentially unstable plaques remains a challenge, and few approaches have been shown to achieve this goal with any reliability even in animal studies. Conversely, many different approaches have been shown to slow the development of atherosclerosis in high fat diet mouse models of the condition. The example here is a demonstration of the degree to which maladaptive fat tissue metabolism contributes to the environment of inflammation and cell stress that accelerates the growth of atherosclerotic plaque. Unfortunately, like so many other approaches, reducing inflammation (via many different means) has not been shown to significantly regress established plaque in and of itself.

Adipocyte dysfunction is closely associated with oxidative stress and chronic inflammation, which contribute to systemic metabolic disturbances and atherosclerosis. We previously identified the NKA (Na/K-ATPase) α1 subunit as a signal transducer that activates Src-family kinases and promotes oxidative stress and inflammation in various cell types, including adipocytes and macrophages. NaKtide, a peptide inhibitor of NKA signaling, has been shown to reduce systemic oxidative stress and inflammation in vivo. In this study, we investigated the role of adipocyte-specific NKA signaling in atherosclerosis.

Adipocyte-specific NaKtide was delivered to Apoe-/- mice using a lentiviral vector under the adiponectin promoter. The mice were then fed a Western diet for 12 weeks to induce atherosclerosis and then assessed for atherosclerotic plaque burden in the aortic arch and at the level of the aortic sinus. Inflammatory and oxidative stress markers were analyzed in adipose tissue and plasma. Adipocyte-specific NaKtide reduced atherosclerotic plaque area by 67% in the aortic arch and by 48% in the aortic sinus. CD68+ macrophage content and α-SMA+ smooth muscle cell content in the aortic sinus were decreased by 45% and 53%, respectively. These vascular improvements were accompanied by dampened adipose tissue inflammation and oxidative stress, improved glucose tolerance, and reduced systemic inflammation.

These findings highlight a critical contributing role for adipocyte NKA signaling in atherosclerosis, suggesting an important endocrine and paracrine influence of adipose tissue on large artery atherogenesis and supporting the therapeutic potential of targeting NKA in cardiometabolic disease.

Link: https://doi.org/10.1161/ATVBAHA.126.325070

Aging is a complex stochastic process of damage accumulation, shaped at the detail level by choices made, environments encountered, and the responses and interactions of countless cells. As the paper here notes, this gives rise to a sizable variance between individuals, even those with the same genetics or similar lifestyles. The research and medical community largely react to this variance with a drive towards developing personalized medicine, but the underlying mechanisms of aging are the same from individual to individual, even if outcomes vary. A therapy that addresses one underlying mechanism in one tissue will tend to produce differing levels of benefit from person to person, but in principle it should always produce benefit. Undergoing some degree of repair should always result in better outcomes than not undergoing repair.

Most human omic studies remain cross-sectional, despite growing evidence that transcriptomic and metabolomic states are temporally dynamic. Cross-sectional designs are limited in their capacity to separate stable interindividual differences from within-participant change and may obscure the degree to which molecular aging varies between individuals. Longitudinal multiomic studies address this gap but are challenging to implement. To address these challenges, we established the MultiMuTHER study within the deeply phenotyped TwinsUK cohort. MultiMuTHER includes repeated whole-blood RNA sequencing and serum metabolomic profiling at three or more time points over up to 8 years in 335 females. We used this resource to ask four questions: which genes and metabolites change over time; how much individual trajectories diverge from population-level trends; to what extent multiomic trajectories are shaped by intrinsic factors including host genetics and cell type composition as well as extrinsic elements such as circadian timing, seasonality, and environmental exposures; and whether transcriptomic and metabolomic changes are coordinated across omic layers.

We identified 5,061 genes and 181 metabolites whose levels changed over time, with participants displaying distinct longitudinal trajectories, sometimes opposite to population-level trends. Longitudinal changes in gene expression exhibited marked cell type specificity, with different patterns in the adaptive versus innate immune compartments. Longitudinally variable genes were enriched for functional categories relevant to aging, including cardiometabolic and neurodegenerative disorders. Gene expression and metabolite levels showed strong context-specificity, with 25% of genes and 24% of metabolites associated with seasonality, and 26 and 39%, respectively, associated with circadian variation.

Our findings show molecular aging to be a dynamic, context-dependent, and highly individualized process. Longitudinal multiomic profiling revealed molecular changes shared across the population and trajectories that diverged between individuals, while highlighting the influence of cell type composition, host genetics, biological rhythms, environmental exposures, and cross-omic connectivity. This study, along with the MultiMuTHER resource, provides a framework for understanding biological aging as a set of interacting molecular trajectories, with utility for future precision medicine efforts.

Link: https://doi.org/10.1126/science.aed6452

Every field of specialist knowledge consists of a series of concentric circles, the greatest knowledge at the center, the scientists advancing the state of the art, and the least knowledge at the outskirts, the public at large. In between we find lesser scientists, patient advocates, laypeople with a strong interest in the field, and so forth - various gradations of knowledge. The members of any given ring engage in an educational dialog with the next ring out, and themselves learn from the education efforts of the more knowledgeable neighboring inner ring. The more distant any two rings are, the less they tend to engage with one another directly.

Thus we end up with the edifice of public messaging, simplifications of scientific knowledge intended for people who will never spend much time delving into a field, and largely constructed by those who are not the most knowledgeable specialists in the field. Some of these simplifications are better than others, depending on the incentives of those creating them. It seems a necessary evil, given the way the world works. We all have the freedom to pursue a greater understanding in the aspects of life and technology that we consider important, but far from enough time to become a polymath. Some shortcuts are necessary in the service of doing some good in the world.

An aging essential 8: closing the gap between geroscience and the public it serves

Longevity medicine has reached an uncomfortable milestone: more clinically credible than at any prior point, and simultaneously more publicly confused. Senolytics, partial epigenetic reprogramming, and GLP-1 metabolic agents have entered human trials within a single decade. Alongside that progress, biological age tests, longevity clinics, and consumer wearables have scaled well ahead of any shared standard governing what they measure or what a person should do with the result. The field has begun to describe this as an implementation gap, in which biological age products and clinics operate ahead of validated standards and regulatory frameworks. The remedies under active discussion are directed at research and clinical infrastructure: standardizing what longevity clinics measure, how they are structured, and which biomarkers and outcomes should count. Few of them address the layer that ordinary people actually encounter, which is a number on an application, a panel of biomarkers, or a clinic promising rejuvenation, with no common framework against which any of it can be read.

The commercial layer is already substantial. Direct to consumer epigenetic age tests are now sold online, longevity clinics offering biological age panels have opened in many cities, and consumer wearables report readiness, recovery, and pace of aging scores derived from proprietary and largely undisclosed algorithms. None of these products share a common scale, none is obliged to demonstrate that its output responds to intervention, and a person who buys two of them may receive two different biological ages with no means of reconciling them. This is the environment into which any public facing instrument would arrive, and it is why such an instrument is worth building and not merely describing.

Cardiovascular medicine encountered a comparable problem and resolved it not with a new therapeutic but with a communication instrument: Life's Essential 8, which distilled a contested risk landscape into eight components scored from 0 to 100, and which has since been shown to track biological aging itself. This perspective argues that geroscience has assembled much of the material for an equivalent instrument, even while the field continues to disagree about foundational questions. Expert panels have converged on which biomarkers are worth tracking as outcomes in aging intervention trials, and have concluded that no single biomarker suffices, which leaves a composite as the only viable path. What has not happened is the translation of that research-level agreement into a public-facing instrument.

Aging clocks built using machine learning techniques applied to biological data are colloquially said to measure biological age, or at least aspire to measure biological age. Biological age is nebulous and debated at the detail level, but a rigorous definition is the increase over time in risk of mortality from intrinsic causes. A greater mortality risk implies a greater biological age, regardless of chronological age. Regarding clocks, it would be more accurate to say that they may measure some reflection of biological age, or factors that correlate with biological age, and it is actually far from clear that any given clock does this in a useful way. The lengthy review and discussion noted here is a good one, and digs into many of the subtle issues in how aging clocks are presently presented.

Biological age (BA) has been proposed as a complementary construct to chronological age (CA) for quantifying interindividual heterogeneity in aging trajectories. Biological aging clocks (BACs) integrate molecular, clinical and multi-omics biomarkers to estimate aging-related phenotypes beyond CA. This narrative review critically examines the biological foundations, statistical methodologies, interpretative challenges and translational applications of BACs. We discuss the mechanistic basis of BACs development within the frameworks of the hallmarks and domains of aging, emphasizing the roles of age-related methylome remodeling, immunosenescence, and chronic low-grade inflammation.

BACs are classified into three major generations according to their training objectives: first-generation clocks optimized to predict CA, second-generation clocks designed to estimate morbidity and mortality risk, and third-generation clocks developed to quantify the pace of aging from longitudinal biomarker changes. We also review multi-omics and artificial intelligence-based approaches that aim to capture the multidimensional nature of aging. Important limitations remain regarding biological specificity, causal interpretation, reverse causation, confounding, generalizability and clinical applicability of BACs. Current evidence suggests that BACs represent distinct operationalizations of biological aging instead of interchangeable measures of a single construct. Future advances will require longitudinal, mechanistic, and diverse population-based studies to improve interpretability, reproducibility, and translational utility.

Link: https://doi.org/10.1016/j.ric.2026.100053

The accumulation of senescent cells is an important contribution to degenerative aging; the inflammatory secretions of senescent cells actively degrade tissue structure and function. Animal studies have shown that selective destruction of senescent cells produces a meaningful degree of rejuvenation in old animals, alongside reversal of the pathology and progression of many age-related conditions. Senescent cells exhibit a sizable number of metabolic differences from normal cells, and researchers continue to explore these differences in search of novel ways to selectively destroy senescent cells. Here find an example of a novel finding, in which researchers explore the increased glycolysis that supports senescent cell energy metabolism and find a way to sabotage it.

Aging is a complex biological process, which is affected by several factors, lifestyle, diet, genetic or epigenetic factors, environmental stress, and metabolisms. Among others, several reports observed increased glycolysis in senescent cells (SnCs) and individual aging, whose causal effects or biological mechanisms have been unclear. Recently, we identified phosphoglycerate mutase 1 (PGAM1)-checkpoint kinase 1 (Chk1) binding as a booster for glycolytic metabolism and cell viability in SnCs.

Secretory phenotype of inflammatory factors, known as senescence associated secretory phenotype (SASP), is one of prominent properties in SnCs, which accelerates chronic inflammation and aging-relevant dysfunctions in tissues. Inhibition of PGAM1-Chk1 binding removes SnCs and suppresses SASP, alleviating organ damage and pulmonary fibrosis in vivo. Thus, PGAM1-Chk1 interaction represents a target for senolysis to preserve resilience in aging.

Link: https://doi.org/10.70401/Geromedicine.2026.0034