Fight Aging!

In order to produce an airtight answer to the question of whether obesity accelerates aging, versus merely being very bad for one's health, one has to have an airtight definition of aging. It is always possible to fall back to the oldest and least useful definition of aging, which is a rise in risk of mortality over time driven by intrinsic causes. Arguably the effects of obesity fit that definition, but then replace the introduction of excess calories with the introduction of infectious viral particles, and suddenly someone will say that if obesity accelerates aging as judged by mortality risk, then a few weeks of influenza infection also accelerates aging by the same measure. Or ingesting outright toxins (dramatically) accelerates aging. This is unsatisfying.

Thus any reasonable discussion of whether obesity accelerates aging has involve a tour of what obesity does to cellular biochemistry, and also has to involve judgement calls on which of those changes are versus are not aging. Everything changes with age. Some of that is cause, some of it consequence. Natural aging is a certain balance of certain harmful mechanisms; if we observe what looks like accelerated aging, and under the hood we see that it is just one or just two of those mechanisms running amok, then is it really accelerated aging? Or is it just poor health resulting from the accumulation of cell and tissue damage? Obesity certainly accelerates the age-related accumulation of senescent cells. But harmful levels of irradiation achieve that outcome as well! A great many things can superficially look like accelerated aging: inefficient DNA repair; slow poisoning; malnutrition; and of course obesity. There is a great deal of room to argue over whether they are in fact accelerated aging or not, but all that debate hinges on how exactly one defines aging.

There is one way in these considerations can be useful, and that is managing expectations as to whether therapies that treat aging are going to be more versus less useful as treatments for various forms of what appear to be accelerated aging. For a therapy to be useful, mechanisms have to align. We know that the apparently dramatically accelerated aging of Hutchinson-Gilford progeroid syndrome (HGPS) is driven by mutation that harmfully alters a critical protein involved in the structure of the cell nucleus. Those protein alterations occur in normal aging to only a small degree. Treatments for aging are thus unlikely to be useful in HGPS and vice versa. Obesity, however, is clearly correlated with an increased burden of senescent cells. Senotherapeutics developed for use in the treatment of aging may well be beneficial for obese individuals even at younger ages.

Obesity accelerates aging: Mechanisms and therapeutic implications

To explore how to delay aging effectively, scientists have summarized twelve aging characteristics that may be slowed, stopped, or reversed through intervention: genomic instability, telomere depletion, epigenetic changes, loss of protein balance, loss of autophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular aging, stem cell depletion, changes in intercellular communication, chronic inflammation, and dysbiosis. The accumulation of these characteristics is associated with an increased prevalence of various age-related diseases. Research indicates that interventions aimed at slowing the aging process can postpone the onset and progression of various diseases in numerous rodent models.

There are intricate and multifaceted connections between obesity and aging. Obesity is associated with a variety of chronic and degenerative diseases, such as type 2 diabetes, osteoarthritis, cancer, and cardiovascular and renal dysfunction, and may lead to premature aging. A large amount of research evidence suggests that obesity can affect the accumulation of various aging biomarkers, including telomere shortening, epigenetic changes, disruptions in protein homeostasis, mitochondrial dysfunction, cellular senescence, stem cell depletion, and alterations in intercellular communication. Meanwhile, interventions aimed at extending health and lifespan, such as calorie restriction and exercise, are associated with reducing obesity.

Undoubtedly, obesity is an accelerator of aging and aging-related diseases, and its intervention directly impacts the development of aging. However, the overlapping characteristics mentioned above merely indicate potential mechanisms by which obesity promotes aging, with the specific molecular mechanisms involved remaining unclear. These findings suggest that future efforts should focus on further exploring these mechanisms and validating them through targeted biological markers to advance precision medicine development.

A sizable body of evidence points to a meaningful role for the accumulation of senescent cells in the onset and development of age-related pulmonary conditions such as idiopathic pulmonary fibrosis. These are conditions characterized by chronic inflammation and harmful structural remodeling in lung tissue. Animal studies suggest that senolytic therapies to clear senescent cells can turn back the course of disease. An initial small academic human trial of senolytic treatment in patients with idiopathic pulmonary fibrosis produced promising results, but little to no follow up has occurred. This is the standard problem for generic drugs and otherwise low-cost therapies: since little profit can be made, no-one can raise sufficient capital to pay for the high costs of clinical trials.

Aging is the primary risk factor for most chronic diseases and is accompanied by the progressive accumulation of senescent cells within tissues. While cellular senescence initially serves as a protective mechanism that limits the proliferation of damaged cells, its persistent presence contributes to tissue dysfunction through the secretion of a broad spectrum of inflammatory and profibrotic mediators. The resulting chronic low-grade inflammation, oxidative stress, immune dysregulation, and impaired regenerative capacity are increasingly recognized as hallmarks of age-related pathology. Chronic pulmonary diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, increase markedly with age and are increasingly regarded as manifestations of accelerated lung aging. Their development and progression are further exacerbated by obesity and type 2 diabetes mellitus, two highly prevalent metabolic disorders characterized by chronic metabolic stress, mitochondrial dysfunction, systemic inflammation, and enhanced accumulation of senescent cells.

Emerging evidence suggests that cellular senescence represents a common biological denominator linking metabolic and pulmonary disease. Through persistent inflammatory and profibrotic signaling, senescent cells establish a self-perpetuating cycle of chronic inflammation, extracellular matrix remodeling, fibrosis, endothelial dysfunction, and impaired tissue repair, thereby driving progressive deterioration of both metabolic and pulmonary function. The recognition of cellular senescence as one of the important drivers of both chronic pulmonary and metabolic diseases has stimulated growing interest in therapeutic strategies aimed at reducing senescent-cell burden or attenuating its detrimental effects. Current approaches include both novel senotherapies specifically targeting cellular senescence, as well as established therapies used in metabolic diseases that have recently been shown to exert senescence-modulating effects. Although clinical evidence remains limited, targeting cellular senescence offers a unique opportunity to address the underlying biology of aging rather than individual disease manifestations.

Link: https://doi.org/10.3389/fragi.2026.1812724

There are now scores of aging clocks in the literature, most of which have come and gone and see little adoption. Most research is focused on gathering more data for handful of mainstream clocks, but these clocks are intended to capture a measure of aging generally across the whole body, keyed to outcomes such as mortality risk. Evidence suggests that different organs and tissues can age at different rates, however. Thus there remains a need for the development and validation of tissue-specific aging clocks. Here, researchers review the present state of development for clocks intended to measure aging in the brain specifically.

Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution.

This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes.

Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging.

Link: https://doi.org/10.1016/j.exger.2026.113260

The major divide in theories of aging lies between the mainstream camp of damage accumulation and antagonistic pleiotropy on the one hand, and the minority camp of programmed aging theories on the other. The damage accumulation camp sees aging as a side-effect of the focus of evolutionary mechanisms on early life reproductive success, favoring the development of biological systems that are front-loaded for early life success, with little investment in maintenance over time. Programmed aging purists view aging as a process that is under active natural selection, however, not a side-effect at all. Why degenerative aging would be selected for is debated, but group selection to reduce the risk of runaway population growth has been argued, as well as the winnowing effect of environmental change on non-aging species, as aging allows for faster adaptation to that change, out-competing non-aging competitor species.

The relatively recently developed hyperfunction theories of aging have a foot in each camp, and might crudely be thought of as a compromise position, though that isn't why they emerged. It has been a difficult area of the field to follow, as it wasn't always clear that everyone involved had the same view of the definition of hyperfunction. Today's open access paper provides a good summary of the consensus hyperfunction view, insofar as such a thing now exists: biological programs that determine early life growth and development continue to operate in adult life in maladaptive ways, and become overtly harmful over time, giving rise to aging. This is roughly a direct conceptual fusion of the concepts of antagonistic pleiotropy and programmed aging. Does any of this theorizing matter? To the degree that it determines research priorities for the development of therapies to treat aging, it probably does.

A brief history of the hyperfunction theory of aging and future directions

Understanding the mechanisms underlying aging processes is crucial for biogerontology and for developing translational approaches. There is much debate, however, regarding the fundamental nature and drivers of aging. The idea that aging arises from genetically encoded processes has gained traction in recent years, the so-called "programmatic theories". It is important not to conflate programmatic and programmed theories, as the latter view aging itself as an evolved adaptation serving a function, while in programmatic theories late-life decline is driven by developmental programs that run-on without aging being adaptive.

In past decades, the idea that aging results from a program or from continued developmental processes became less popular. The evolutionary theory of aging argued against a programmed (i.e., adaptive) aging process, predicting that such a program would be selected against. The dominant view was that aging arises from the declining force of natural selection with age, the so-called "selection shadow". In this model, both genetic variants with detrimental late-life effects, or variants beneficial early in life but harmful later, can become fixed in populations, contributing to aging; here, aging is not an adaptation and, in that sense, not programmed.

The increasing emphasis on molecular damage in aging research was likely driven, at least in part, by advances in molecular biology and biochemistry. The explosion of molecular discoveries in the second half of the 20th century revealed a vast and intricate number of cellular components and biological processes, which in turn led to a proliferation of theories linking aging to defects in each of these many processes. Because virtually any important biochemical or molecular process can malfunction and become harmful to cells, it is easy to conceive new damage-based theories of aging. This abundance of molecular detail reinforced the perception that aging is driven by stochastic damage and led to many theories and frameworks positing damage accumulation as the root cause of aging. It was against this trend that a new wave of programmatic theories emerged at the start of the 21st century.

In 2006, a seminal conceptual paper proposed the quasi-programmed theory of aging, introducing the term hyperfunction. It proposed "a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging." While acknowledging that damage occurs with age, it was argued that such damage plays a negligible role in determining lifespan. Instead, quasi-programs are the principal drivers of aging and limiting human lifespan.

Although programmatic theories, such as hyperfunction, provide powerful conceptual frameworks for understanding the aging process, much work remains to be done. They are still outside the dominant geroscience paradigms, such as the "hallmarks" and "pillars" of aging. The unfortunate consequence - I would argue - is that most aging studies focus exclusively on adult life, hindering efforts to connect aging to developmental processes. If aging processes follow trajectories set early in life, then studying the whole life course is imperative to elucidate aging mechanisms. Besides, if repair and maintenance mechanisms are downregulated during development, then studying early development may prove valuable for identifying rejuvenation therapies, as already demonstrated in partial reprogramming.

Iron metabolism is strongly connected to oxidative stress, the excessive production of reactive oxygen species and other oxidative molecules that outpaces the ability of cells to avoid, resist, or repair the consequent damage. It can lead to a form of programmed cell death called ferroptosis. Here, researchers describe how iron metabolism and ferroptosis are seen to contribute to the development of atherosclerosis. This isn't a very well developed area of research into cardiovascular disease, in that while one can paint an interesting mechanistic picture at the high level, much of the detail remains to be filled in, and robust forms of therapy based on manipulation of iron metabolism or ferroptosis have yet to emerge.

Disturbances in iron homeostasis have a bidirectional impact on the development of atherosclerosis. The classic "iron hypothesis" states that systemic iron overload increases the risk of cardiovascular diseases (CVDs), while controlling iron deficiency can protect blood vessels. Histopathological studies have confirmed that atherosclerotic plaques have a higher iron deposition compared to healthy blood vessels, and this phenomenon can be observed from the early stages of atherosclerosis. Macrophages recycle iron from senescent red blood cells, and intra-plaque hemorrhage exacerbates the phagocytosis of red blood cells, which is considered a key mechanism for iron deposition.

An increase in intracellular iron concentration enhances the uptake of oxidized low-density lipoprotein (ox-LDL), hinders cholesterol efflux, and accelerates the formation of foam cells in the plaque environment. This process leads to a decrease in GPX4 expression, an excessive production of reactive oxygen species (ROS), and an exacerbation of lipid peroxidation - all three together exacerbate intracellular oxidative stress, directly aggravating endothelial dysfunction and ultimately increasing plaque instability.

Despite the promising therapeutic potential of targeting ferroptosis discussed throughout this manuscript, several important limitations must be acknowledged. First, the disease specificity of ferroptosis-driven pathology remains incompletely defined; not all conditions involving cell death or oxidative stress may benefit from ferroptosis inhibition, and the contribution of ferroptosis varies substantially across different diseases and even across stages of the same disease. Second, the optimal timing of intervention is challenging to determine, as ferroptosis may play divergent roles in early versus late disease phases, and premature or delayed intervention could be ineffective or even detrimental. Third, systemic modulation of iron metabolism carries risks of off-target effects on other organs, including potential hepatotoxicity, cardiotoxicity, and disruption of normal iron homeostasis in tissues with high iron turnover. Fourth, while natural compounds are often proposed as ferroptosis modulators, they have pharmacological limitations such as poor solubility, low bioavailability, off-target bioactivity, and unknown long-term safety profiles.

Link: https://doi.org/10.1016/j.redox.2026.104330

That we cannot accurately and robustly measure biological age is a major impediment to the development of rejuvenation therapies. Without the ability to quickly focus on approaches with the largest effects on biological age, the field spends far too much time on marginal classes of therapy, and optimization of any given approach is challenging, haphazard, and slow. The development of aging clocks in recent years is a step in the right direction, but clock data is not trustworthy in the matter of assessing the effects of any given intervention until they are fully calibrated to that intervention via life span studies - which defeats the point of having a fast clock measure. That this is a problem is widely appreciated in the field of aging research, so we might hope that we will see meaningful progress towards reliably and accurate measurement of biological age in the years ahead.

Aging is a major risk factor for numerous chronic diseases and a leading contributor to global mortality. Slowing the rate of aging would have revolutionary implications for health and longevity. A fundamental barrier to achieving this goal, however, is the difficulty of accurately measuring the effects of rejuvenating interventions. The development of precise gerontometric methods, therefore, is a priority for both science and preventive medicine.

metabolomics. Although metabolomic approaches have limited accuracy in determining biological age, the described approach, which averages multiple metabolites from a large metabolomic signature of aging, circumvents this limitation. It allows for measurement of biological age change with an accuracy of approximately one month. Such precision gerontometry enables accelerated testing of candidate anti-aging interventions, helping to eliminate ineffective ones, speed the development of effective ones, and ultimately extend the duration of healthy human life, with profound social and humanitarian benefits.

Link: https://doi.org/10.3390/metabo16070463

Alzheimer's disease, and the other common age-related neurodegenerative conditions, are characterized by chronic inflammation in brain tissue. Aging in general is characterized by an increased level of constant inflammatory signaling. Numerous different mechanisms contribute to this constant inflammation, such as maladaptive reactions to mitochondrial DNA fragments released into the cytoplasm as a result of age-related mitochondrial dysfunction, and a growing burden of senescent cells that actively secrete pro-inflammatory signals. The gut microbiome changes in ways that provoke inflammation as well, and the intestinal barrier becomes leaky with age, allowing more unwanted bacteria and bacterial metabolites into the body. In the brain, clearance of metabolic waste is achieved in large part by circulation of cerebrospinal fluid and its drainage into the body via channels that atrophy or become dysfunctional with age. Reduced flow allows metabolic waste to build up in brain tissue, including the protein aggregates associated with neurodegenerative conditions - and all of this increases maladaptive inflammatory responses on the part of immune cells in the brain.

Any reasonably complete list of contributions to age-related inflammation is much longer than the few high points noted above. Comprehensively dealing with the inflammation of old age is a task that will require more than one therapy, if the objective is to remove the causes. This is perhaps why much of medical research tends to favor sabotaging inflammatory signaling or aspects of immune cell function rather than addressing causes. It is a bad long term strategy from the point of view of achieving radically better human health, but it works in the short term to get drugs approved and investors their profits. The therapy that is the subject of today's open access report on its initial clinical trial results is an example of the dominant class of approach to chronic inflammation - find a central mechanism involved in coordinating the inflammatory response, and sabotage it. Unfortunately the initial data suggests that this particular anti-inflammatory therapy may not work as well in humans as it does in mouse models of inflammatory neurodegeneration.

Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial

While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with fragment crystallizable (Fc) region-effector silencing and reduced neonatal fragment crystallizable receptor (FcRn) binding (IBC-Ab002) was engineered.

Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1 mg/kg to 30 mg/kg), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg/kg dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD.

Mitochondrial transplantation is a promising approach to treating age-related mitochondrial dysfunction. Cells readily take up mitochondria from their surroundings. The major challenge in the development of practical mitochondrial transplantation therapies is the robust production of the large numbers of mitochondria needed for a human therapy. Ways to improve the survival and uptake of mitochondria are thus helpful because they reduce the manufacturing burden, lowering the number of mitochondria needed for a successful treatment. Researchers here upon tools used in lipid nanoparticle therapies and gene therapies and demonstrate that they can be used to improve the delivery and uptake of mitochondria into cells in tissues.

Mitochondrial transplantation has emerged as a promising strategy for modulating cellular bioenergetics in mitochondrial dysfunction. However, isolated mitochondria suffer from poor stability and limited cellular uptake, restricting their therapeutic application. To address these limitations, we developed a surface engineering strategy that stabilizes isolated mitochondria while enabling interactions with target cells, providing a platform for selective organ- and cell-targeting. Polyethylene glycol (PEG) with lipid/carbon chains was introduced to mitochondria-associated membrane structures, forming a protective hydration layer on the mitochondrial surface. This PEG layer also serves as a modular platform for functionalization with biomolecules, such as peptides and antibodies, thereby broadening its biomedical applications.

In this study, we examined whether mitochondrial function in target cells can be modulated using PEG-shielded mitochondria functionalized with a cell-penetrating peptide (CPP) via a maleimide linkage. Our results suggest that CPP-PEG-modified mitochondria exhibit efficient cellular internalization and are associated with increased mitochondrial respiratory activity, consistent with intracellular bioenergetic modulation. These findings suggest that spatially controlled presentation of CPP at the terminus of a PEG layer may provide an effective approach for stabilizing isolated mitochondria while modulating intracellular dynamics and functional responses. This surface engineering strategy offers a proof-of-concept design framework for mitochondria-associated engineering and future bioenergetic strategies.

Link: https://doi.org/10.1002/admi.70583

The bacterial species P. gingivalis is a cause of periodontitis, a common form of inflammatory gum disease that in addition to damaging gums, teeth, and bone in the mouth, also contributes to the development of inflammatory age-related conditions elsewhere in the body. Here researchers report on a novel approach to selectively removing P. gingivalis from the mouse, using a combination of a photosensitive dye conjugated to an antibody that binds to surface features on this species of bacteria. When irradiated with near infrared light, this kills the targeted cells. Treating a mouse model of periodontitis in this way successfully reduced inflammation and resolved the condition.

Traditionally, periodontitis was viewed as a simple infection; however, it is now recognized as a complex polymicrobial disease driven by synergistic interactions within the oral microbiota and a subsequent aberrant host immune response. Periodontitis is typically initiated by a shift from symbiotic to dysbiotic microbial communities. In this process, 'keystone pathogens' such as Porphyromonas gingivalis, even at low abundance, can remodel the surrounding commensal bacteria into a highly inflammatory state.

Recently, a new cancer-targeted therapy called near-infrared photoimmunotherapy (NIR-PIT), which combines antibody-dye conjugates and near-infrared light, has emerged. The cell death mechanism of NIR-PIT is unique. Specifically, when the conjugate is irradiated with near-infrared light in the presence of sufficient electron donors, the hydrophilic side chain (silanol) of the IR700 molecule dissociates through a photochemical ligand reaction, and the remaining structure, including the antibody, rapidly becomes hydrophobic and aggregates. At the same time, the antibodies bound to the surface antigens also aggregate on the tumor cell membrane. The aggregation reaction of IR700 causes physical stress on the antigen-antibody complex and selectively destroys the target cells

We recently developed NIR photoantimicrobial-targeted therapy (NIR-PAT2) to treat infectious diseases. For NIR-PAT2, as targeting molecules, we exploit immunoglobulin Y (IgY). NIR-PAT2 with IgY could be used for body surface and lumens, such as skin, hair, eye, digestive tract. The aim of this study was to develop a bacteria-targeted therapeutic modality using NIR-PAT2. While we acknowledge the inherent limitations of single-pathogen targeting in a complex polymicrobial disease, we hypothesized that selectively eliminating a keystone species would disrupt the synergistic drivers of dysbiosis. We define this approach as a precision-modulating therapy, designed to selectively ablate P. gingivalis while preserving the ecological integrity of the oral community. Here, we demonstrate that NIR-PAT2 successfully modulates oral dysbiosis, leading to the resolution of periodontitis and the restoration of a healthy-associated microbial profile in a murine model.

Link: https://doi.org/10.1186/s12967-026-08336-2

Telomeres are repeated DNA sequences found at the ends of chromosomes. A little telomere length is lost with each cell division, and short telomeres trigger cell senescence or programmed cell death. It is a part of the system ensuring the Hayflick limit on the replication of somatic cells. The stem cells that create replacement somatic cells can lengthen their own telomeres, but there are very few stem cells in comparison to the number of somatic cells making up the majority of tissue. This is how evolution reduces cancer to an acceptable level, by dramatically restricting the number of cells capable of unfettered replication, and thus reducing the odds of a malfunction leading to runaway replication.

With age stem cell function declines, reducing the pace at which stem cells deliver replacement somatic cells with long telomeres. As a result, average telomere length falls and the proportion of cells with very short telomeres increases in tissues throughout the body. This has a meaningful negative effect on health, a driver of chronic inflammation, increased numbers of senescent cells, and impaired tissue function. In today's open access paper, researchers report on their efforts to specifically sabotage the cascade of mechanisms that emerge in response to short telomeres in a cell, showing that it improves health in aged mice, at least in the short term. The flip side of the coin, not investigated here, is that this could increase cancer risk by promoting damage to DNA via the continued operation of damaged cells, usually avoided because cells with very short telomeres are destroyed on some timescale.

Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging

Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. When critically short, telomere ends are detected as DNA damage and trigger a telomeric DNA damage response (tDDR), a signaling cascade involving posttranslational protein modifications, such as phosphorylation of histone H2AX at serine 139 (known as γH2AX), which promotes recruitment of DDR factors including phosphorylated KRAB-associated protein 1 (pKAP1) at damaged sites. Persistent tDDR drives cellular senescence and cell death. The inability of senescent cells to proliferate impairs tissue regeneration, and their secretion of proinflammatory factors, collectively known as the senescence-associated secretory phenotype, promotes chronic, low-grade inflammation, disrupting the local microenvironment and eventually causing systemic frailty.

Whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Telomerase RNA component (TERC) knockout mice, which recapitulate telomere-driven hematopoietic dysfunction and aging, that targeting telomeric noncoding RNAs with telomeric antisense oligonucleotides (tASO) suppresses tDDR in hematopoietic organs, reduces senescence and inflammation, alleviates hematopoietic dysfunction, and enhances hematopoietic stem cell fitness and repopulating potential in vivo. Similar observations were recapitulated in aged wild-type mice, and ex vivo treatment with tASO improved the function of human hematopoietic stem cells from aged donors.

Taken together, our results identify tDDR as a pathogenic driver of hematopoietic decline and support tASO-mediated tDDR inhibition as a potential therapeutic strategy for telomere biology disorders and age-associated hematopoietic aging.

Technically, even very small effects can be classed as rejuvenation if they move the right markers, if they in some way reduce the burden of damage and dysfunction of aging. Exercise probably rejuvenates to some degree, by any reasonable definition. Yet we know the bounds of the possible when it comes to exercise and other widely used interventions, and the outcomes are nowhere near as large as we would like. Fit people are still aging to death, and end up frail in the later stages of life.

In the matter of restoring lost function to the hematopoietic stem cell populations of the bone marrow that are responsible for generating the cells that make up the immune system, there are a number of interventions that have been shown to outperform the effects of exercise in mice. One of the more interesting examples is the results of a single treatment of CASIN, which improves stem cell function globally, improves immune function, and extends life. Restored immune function is an important goal in the treatment of aging, given the sizable influence the immune system has over the course of aging.

Aged hematopoietic stem cells (HSCs) are characterized by increased phenotypic number, decreased self-renewal and long-term reconstitution capacity, myeloid-biased differentiation, and clonal hematopoiesis. In this review, we summarize the life cycle of HSCs, integrate recent advances in understanding the cell-intrinsic and extrinsic mechanisms that drive HSC aging, and highlight innovative rejuvenation strategies that could be harnessed to delay HSC and systemic aging.

Exercise enhances systemic health through improved circulation and metabolism. However, it was found that exercise has little effect on rejuvenating HSCs. It is plausible that exercise preferentially accelerates lymphopoiesis via niche remodeling rather than directly rejuvenates aged HSCs. Dietary restriction (DR) modulates HSC function through multiple nutrient-sensing pathways. Pharmacological approaches targeting the same metabolic pathways also show rejuvenation effects on HSCs. Nicotinamide riboside (NR) enhances mitochondrial function and restores the metabolic competence and regenerative capacity of aged HSCs. Similarly, mTOR inhibition with rapamycin reverses age-related functional decline of HSCs, improving self-renewal, reconstitution potential, and antiviral immunity in aged mice.

Sirt3 is a mammalian deacetylase that exhibits age-dependent expression decline in HSCs. Sirt3 knockout in aged mice impairs HSC self-renewal capacity, while its overexpression enhances regenerative potential. Sirt7 deletion induces premature activation, lymphoid differentiation bias, and functional exhaustion of HSCs. In contrast, Sirt7 overexpression reverses these aging hallmarks, and restores balanced lineage output and reconstitution capacity in geriatric murine models. Transient expression of Yamanaka factors (e.g., Oct4, Sox2, Klf4, and c-Myc) showed systemic rejuvenation effects and extended life span in mice, whether it can reverse HSC aging remains to be tested.

A marked increase in non-polarized cells is observed among aged HSCs, attributed to elevated Rho-GTPase activity of Cdc42 during aging. Casin, a small-molecule Cdc42 inhibitor, restored the proportion of polarized HSCs in aged mice and moderately enhanced their long-term reconstitution potential. In vivo Casin treatment significantly extended the lifespan of aged mice and reduced systemic inflammatory cytokines. Aged HSCs exhibit MMP reduction and pronounced mitochondrial heterogeneity, with low-activity subpopulations displaying characteristic aging phenotypes. Mito-Q treatment in aged mice partially restored MMP and augmented transcriptional activity in HSCs.

Oral administration of the senolytic drug ABT263, an inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL, effectively cleared senescent HSCs, ameliorated irradiation-induced premature hematopoietic aging, and partially restored the regenerative ability of HSCs.

Link: https://doi.org/10.1186/s13059-026-04119-6

Researchers here discuss a bidirectional relationship between age-related alterations in bile acid metabolism, centered in the liver, and changes in the composition of the gut microbiome. These changes take place in the context of increasing dsyfunction of the intestinal barrier with age, allowing unwanted bacteria and bacterial metabolites into the body to provoke chronic inflammation and other dysfunction. Researchers have demonstrated in animal studies that restoration of a youthful gut microbiome composition can improve health and extend life; an interesting question is the degree to which restoration of a youthful bile acid metabolism can achieve similar outcomes.

Bile acids (BAs), byproducts of cholesterol metabolism in the liver, are not only vital for lipid digestion and absorption of lipid-soluble vitamins but also act as signaling molecules influencing aging, inflammation control, immune homeostasis, and tumor development. They regulate gut microbiota growth and composition, while gut microbiota significantly influence BA hydrolysis and the synthesis of secondary and tertiary BAs. This interplay affects immune function and metabolic phenotypes, and may contribute to obesity, diabetes, non-alcoholic fatty liver disease, inflammatory bowel disease, and certain cancers.

100 elderly and 100 young participants were enrolled in this study. Fecal and serum BAs were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while gut microbiota composition was assessed through 16S rRNA gene sequencing. Elderly participants exhibited significantly lower levels of primary fecal BAs, particularly cholic acid (CA) and chenodeoxycholic acid (CDCA), alongside an increase in secondary BAs such as lithocholic acid (LCA), leading to a marked reduction in the primary/secondary BAs ratio.

Serum showed a decline in both conjugated and unconjugated BAs, primary/secondary BAs ratio, while a notable rise in 12α-OH/non-12α-OH BAs. Furthermore, increased levels of P21, LPS, IL-6, and TNF-α in the elderly were associated with specific BA changes, including reduced fecal unconjugated primary BAs and increased LCA. Significant differences in gut microbiota composition were observed, with the elderly displaying a higher abundance of microbiota capable of 7α-dehydroxylation. Correlations were observed among BAs, gut microbiota alterations, and markers of chronic inflammation and intestinal barrier dysfunction.

In conclusion, aging is associated with significant changes in the BA pool, which are associated with gut microbiota dysbiosis. These alterations may be related to intestinal barrier dysfunction and chronic low-grade inflammation. Modulating BA metabolism presents a potential strategy for mitigating the aging process.

Link: https://doi.org/10.3389/fragi.2026.1741360

Reduced protein intake is robustly demonstrated to improve long-term health and slow aging in animal studies, and the human evidence is supportive. Many of the sensors and triggers of the beneficial metabolic response to fasting and other forms of calorie restriction react to protein availability specifically, increasing cellular maintenance activities to improve cell and tissue function. "Protein" in dietary matters usually means essential amino acids, those not manufactured in the body. The actual definition that leads to a measurement reported on a food label is more complicated than this, but is still largely an attempt to reflect availability of essential amino acids per ingested unit of a given food type.

As researchers point out in today's open access paper, despite the strong evidence for lower protein intake to be favorable over the long term, government bodies continue to recommend higher protein intake, driven by ongoing concerns over the prevalence of obesity (high protein intake tends to reduce overall calorie intake) and frailty (high protein intake tends to increase muscle growth). There is also the point that not all protein sources are the same from a health perspective. For example, obtaining protein from plant sources is well established to produce better effects on health than protein from animal sources. Further, the intake level of different essential amino acids have different, overlapping effects on health. There is quite a deep rabbit hole underneath the simple point that lower protein intake should be considered beneficial, and researchers here attempt to explore some of it.

Reviewing What is Known of the Ability of Reduced Protein Intake to Slow Aging

In rodents, the ratio of dietary macronutrients profoundly impacts lifespan, with low-protein, high-carbohydrate diets extending lifespan and improving metabolic health. A low-protein diet, also referred to as protein restriction (PR), is a robust geroprotective regimen that lowers total dietary protein intake while still meeting nutritional needs. PR improves healthspan and increases the lifespan of yeast, flies, and rodents. Despite these findings, human dietary recommendations generally suggest increasing protein intake. While the official Recommended Dietary Allowance (RDA) for protein is 0.8 g/kg of bodyweight regardless of sex or age, intakes of 1.0-1.2 g protein/kg of bodyweight are routinely recommended for individuals over the age of 65 to prevent sarcopenia and frailty, and the most recent Dietary Guidelines for America suggest 1.2-1.6 g protein/kg of body weight. These recommendations are supported by studies finding that short-term high protein diets promote weight loss, largely by promoting satiety and reducing food intake in highly compliant subjects.

However, accumulating evidence challenges the idea that higher protein intake is beneficial. Human association studies have found that high-protein diets are associated with an increased risk of diabetes, cancer, and mortality, as well as an increased risk of death due to cardiovascular events. An analysis of the National Health and Nutrition Examination Survey (NHANES) data found that higher protein consumption correlates with increased mortality and age-associated disease incidence, including diabetes.

Randomized controlled trials (RCTs) support the metabolic benefits of PR in humans. We reported that individuals consuming a low-protein diet for 43 days exhibited decreased body weight and fat mass and reduced fasting blood glucose despite increased caloric intake, mirroring our findings in rodents. A recent study in lean men found that a 5-week PR intervention improves insulin sensitivity and increases energy expenditure.

In this review, we detail, for the first time, the hallmarks of PR: improved metabolic health, induction of nutrient-sensing pathways, decreased senescence, improved mitochondrial function, altered epigenome, and the promotion of healthy aging. Taken together, these hallmarks describe the robust impact of PR on aging-related phenotypes. While these hallmarks are seen in most organisms on dietary PR, some variations exist based on biological sex or animal strain. The hallmarks discussed in this review are highly interconnected, providing a firm foundation for future exploration on the causal nature of these hallmarks to understand which hallmarks are most important in orchestrating the response to PR.

Calorie restriction mimetic drugs reproduce some (usually small) fraction of the beneficial metabolic changes that take place with a reduced calorie intake. An increase in the efficiency of the cellular maintenance processes of autophagy appears to be the crucial point. Researchers here report on their assessment of the alterations produced by the small number of calorie restriction mimetics with robust evidence to slow aging and extend life in mice. This part of the research field seems quite capable of generating any number of treatments that will likely work in humans, but unfortunately from what we know of the effects of calorie restriction, this class of therapy is unlikely to produce a large increase in life span in our species. Short-lived species exhibit a much greater extension of life in response to these metabolic manipulation strategies than is the case in long-lived species. This makes sense from an evolutionary perspective: if the calorie restriction response exists because it helps individuals to survive a seasonal famine to reproduce in later times of plenty, then short-lived species will evolve a much greater plasticity of life span. A season is a much larger fraction of the life span of a mouse than it is of a human.

The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17α-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic profiles can identify treated mice as likely recipients of a lifespan-extending intervention well before survival differences emerge. A leave-one-intervention-out procedure confirmed that models trained on any four interventions successfully classified mice from a fifth, unseen intervention, implying shared metabolic alterations across mechanistically distinct treatments.

The most influential metabolites - defined as the minimum set explaining 50% of cumulative model gain - differed substantially across tissues. Only ergothioneine, a dietary antioxidant, ranked highly in more than two tissues: it was elevated by all five interventions in plasma and brain, and by four of five in muscle. Enrichment analyses further identified coordinated remodeling of lipid classes in plasma, perigonadal fat, and kidney. These findings reveal tissue-specific metabolic reprogramming shared across mechanistically distinct longevity interventions and, pending validation against interventions that do not extend lifespan, suggest a path toward metabolomic screening of candidate anti-aging drugs.

Link: https://doi.org/10.64898/2026.06.24.734388

The major hormones produced by the thyroid gland are broadly influential on metabolism and the function of many organs, and thyroid dysfunction is common enough in later life for this aspect of human biochemistry to be very well studied. A range of different unpleasant outcomes and named diseases arise from various imbalances in the production of thyroid hormones. Here, researchers take a particular type of thyroid behavior known to the medical community as non-thyroidal illness syndrome and reframe it as a part of the evolved response to calorie restriction that acts to slow aging - though as it is usually observed in practice by physicians, during times of acute illness, it may be maladaptive.

Non-thyroidal illness syndrome (NTIS), historically termed euthyroid sick syndrome, is characterized by reduced serum triiodothyronine (T3), variable thyroxine (T4), and typically normal or suppressed thyroid-stimulating hormone (TSH) in the absence of intrinsic thyroid disease. Traditionally viewed as an adaptive response to acute illness that does not require intervention, NTIS is increasingly being recognized within broader contexts of metabolic adaptation, including aging, caloric restriction, and pharmacologically induced weight loss. This narrative review reexamines NTIS as a context-dependent metabolic reprogramming response that may represent an evolutionarily conserved survival and longevity mechanism.

Evidence from critical care endocrinology, mitochondrial biology, aging research, caloric restriction studies, and emerging data on glucagon-like peptide-1 (GLP-1) receptor agonists is synthesized to explore the mechanistic and clinical implications of low T3 states. During acute physiologic stress, including infection, trauma, and starvation, reduced peripheral T4-to-T3 conversion and increased reverse T3 production appear to promote metabolic downshifting through decreased mitochondrial oxygen consumption, reduced anabolic signaling, and the redistribution of energy toward immune defense and cellular repair. These adaptations parallel pathways associated with enhanced metabolic efficiency and longevity. Similar thyroid hormone changes are increasingly observed in individuals undergoing significant weight loss, sustained caloric restriction, or GLP-1 receptor agonist therapy.

While transient reductions in T3 may reflect adaptive energy conservation, persistent low T3 states in the setting of chronic inflammation, cardiometabolic disease, sarcopenia, or advanced aging may contribute to impaired mitochondrial function, reduced metabolic flexibility, and loss of physiologic resilience. NTIS may therefore represent a spectrum of adaptive and maladaptive responses influenced by physiologic context, duration, and inflammatory burden. A systems-based, longevity-oriented framework may improve the interpretation of low T3 states and help guide future research aimed at distinguishing beneficial metabolic adaptation from pathologic endocrine suppression.

Link: https://doi.org/10.7759/cureus.110397