Fight Aging!

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

Anti-aging medicine has long been a small specialty field of practice culturally adjacent to sports medicine, but considerably less rigorous and more derided by the mainstream. The present development of a longevity industry, based on means to slow and reverse aspects of aging conclusively demonstrated in laboratory animals and now slowly making their way towards the clinic, is going to have interesting effects on the field of anti-aging medicine. Over some period of time, anti-aging medicine will become reputable, a field in which physicians manage the delivery of treatments for aging that actually work. The field will swell to become the majority of all medical practice, as the majority of all serious illness and death is age-related.

Initially, this growth and takeover of mainstream medicine will look fairly prosaic, as it will likely occur in advance of the availability of any very impressive therapies. It will be built on lifestyle choice, weight management, and calorie restriction mimetic drugs like rapamycin, and the involvement of governments will be driven primarily by the desire to reduce the burden of ever expanding entitlement spending in an aging population. The really interesting therapies and outcomes will arrive later, finding a system ready and waiting for them. As an example of what this early transition will look like, one might read today's open access position paper on the Italian health system, proposing the changes needed for an effective focus on aging.

Towards integration of healthspan strategies into the Italian National Health Service

Italy currently ranks among the world's oldest nations, with adults aged ≥65 years accounting for 24.1% of the population - the highest proportion in the EU - and a projected median age of 51 years by 2050. While life expectancy at birth reaches 85.4 years for women and 81.4 for men, Healthy Life Years amount to only 69.6 and 68.5, respectively, documenting a substantial lifespan-healthspan divide. The prevalence of multimorbidity and disability exceeds 60% in adults aged ≥75 years; women bear a disproportionate share of this burden, both as patients and as caregivers. Meanwhile, the Italian National Health Service (Servizio Sanitario Nazionale, SSN) remains hospital-centric, regionally fragmented, and predominantly reactive, with prevention accounting for a historically modest share of total expenditure.

Against this background, longevity medicine is an emerging, prevention-oriented discipline that aims to extend healthspan - defined here as the portion of life lived in good health, with preserved physical and cognitive function and without significant disability or multimorbidity. It integrates multi-omic biomarkers, digital monitoring, adaptive trial methodology, and life-course risk stratification within a translational framework. Although most constituent tools remain at an exploratory or surrogate stage, and clinical utility has yet to be established, the emphasis on early intervention and precision prevention offers potential to reduce the accumulation of age-related disease and ease long-term pressure on the SSN.

This position paper analyzes Italy's demographic and epidemiological trajectory, examines the structural constraints of the SSN, and outlines the scientific foundations of longevity medicine. It advocates for multidisciplinary translational research and identifies five strategic investment priorities: (i) clinically validated biomarkers of biological age; (ii) interoperable digital monitoring platforms; (iii) Bayesian adaptive multimodal trials; (iv) explainable-AI risk stratification tools; and (v) longevity-informed curricula in medical training. These proposals should be regarded as a staged agenda for evaluation; their relevance will depend on whether they deliver measurable gains in patient-relevant outcomes, feasibility, and cost-effectiveness within the SSN.

Questions regarding the relative importance of different mechanisms and dysfunctions to the progression of aging and eventual mortality are hard to answer definitively. Even given a straightforward class of therapies to target one specific mechanism of aging in isolation of all others, such as senolytics to clear lingering senescent cells, one still has to look at a lot of different studies, extrapolate from mice to humans, and the answer is fuzzy. The other sort of fuzzy answer comes from statistical techniques applied to large longitudinal human epidemiological data sets: compare humans who exhibited different levels of the mechanism in question, and see what happened to them over time. That is the approach taken here in the matter of the chronic inflammation as a driver of aging and age-related mortality. As you can see, the answer produced is a sizable range, arguably not all that informative.

Global population aging underscores the urgent need for biomarkers quantifying biological aging trajectories. While DNA methylation-derived pace of aging (DunedinPoAm) measures individual differences, its generalizability across diverse populations and mechanistic links to systemic inflammation remain underexplored. This study aimed to systematically examine the longitudinal associations between the DunedinPoAm and all-cause mortality in a multiethnic cohort, and to quantify the extent to which systemic inflammatory biomarkers mediate these associations using causal mediation analysis.

For this cohort study, information on a nationally representative cohort of 21,004 U.S. adults was extracted from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2002. Data were analyzed from 2,532 participants, with a mean follow-up duration of 18.5 ± 1.29 years. Higher DunedinPoAm quartiles exhibited graded mortality risks (Q4 vs. Q1: hazard ratio, HR = 2.50), which persisted after multivariable adjustment. Restricted cubic splines revealed a non-linear association, indicating the presence of threshold effects. Systemic inflammation mediated 2.33% to 23.5% of the mortality risk associated with DunedinPoAm, driven by CD4+ T cells, B cells, CRP and comprehensive inflammatory indices. A significant interaction with diabetes underscored metabolic dysregulation as a vulnerability factor.

Link: https://doi.org/10.1186/s13148-026-02206-w

The heart regenerates poorly in comparison to other tissues, and the maladaptive inflammation that occurs following a heart attack does not help the situation. Fibrosis and scarring occurs in inflamed heart tissue, causing loss of function and heart failure. Stem cell therapies and the use of exosomes derived from stem cells are well demonstrated to reduce unwanted inflammation in animal studies, and are fairly widely used in the medical tourism industry. Here researchers report on the assessment of the ability of an exosome therapy to reduce heart failure following an induced heart attack in pigs, showing that it reduces the formation of scar tissue and helps to maintain heart function.

Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation.

The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFRβ)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization.

In a clinically relevant porcine ischemia-reperfusion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFRβ-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.

Link: https://doi.org/10.1016/j.stem.2026.07.003

Cells become senescent throughout life, because of stress or damage or reaching the Hayflick limit on replication, but senescent cells only begin to accumulate with age. When a cell becomes senescent, it grows in size, ceases to replicate, and turns its energies to creating signals promoting inflammation and growth. The immune system is responsible for destroying senescent cells after they have served their purpose, which is usually to attract the attention of immune cells to locations where they are needed to prevent or repair issues. While clearance of senescent cells is efficient in young people, it becomes much less efficient with age, allowing a population of lingering senescent cells to grow over time in tissues throughout the body. The pro-growth, pro-inflammatory signals that are helpful in the short term become harmful when sustained over the long term, disruptive to tissue structure and function and helping to promote the damaging state of chronic inflammation that is characteristic of later life.

Senolytic therapies to selectively destroy senescent cells exist, such as the dasatinib and quercetin combination, but are not widely used, conclusive clinical trial data has not yet been generated, because these are low cost drugs and supplements. No-one can make enough money from them to justify investment in large clinical trials. Meanwhile many companies are working to develop novel, patent-protected senolytic therapies that will be able attract sufficient funding for conclusive clinical trials, and those will be the (much more expensive) drugs that make their way into widespread use. This is the way that modern regulated medicine works.

Meanwhile, another faction of the research community is more interested in finding ways to suppress the inflammatory signaling of senescent cells rather than destroy them. This approach also has its low cost drugs, such as rapamycin, that are unlikely to be the subject of very large clinical trials for their ability to suppress the bad behavior of senescent cells any time soon. Nowhere near as many companies are actively working on novel drugs to alter senescent cell behavior, but the academic research community is identifying new possibilities at a fair pace. Today's open access paper, for example, describes a novel way in which mitochondria support the generation of inflammatory signaling by senescent cells, which opens up a few possible targets for careful sabotage.

Mitochondrial metabolism and epigenetic crosstalk drive SASP

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP). Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes.

Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation, and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

Researchers here restricted old mice to eating only during the 12 hours of the day in which they are usually inactive or asleep, for three days every week, and continued this restriction for a period of 8 weeks. The mice placed on time restricted feeding exhibited improved muscle function versus those who could eat at all times of the day. Studies of reduced or time restricted food intake tend to converge on the concept that benefits derive from spending some amount of time in a state of hunger, however that is achieved. Low nutrient availability triggers a range of adaptive processes in cell behavior, including increased cell maintenance activities. The result is improved cell function, improved tissue function, and a slowing of the pace of aging. While short-term effects are quite similar across species, the effect on pace of aging over the longer term is far larger in short-lived species than in long-lived species.

Sarcopenia, defined as the age-related decline in skeletal muscle mass and function, markedly reduces physical performance, threatens functional independence, and diminishes quality of life in older adults. Although the clinical manifestations of sarcopenia typically emerge later in life, underlying molecular alterations, particularly within the mitochondrial network, occur well before symptom onset. Growing evidence indicates that dietary interventions, including caloric restriction as well as changes in meal timing, composition, and overall intake, play a critical role in attenuating age-associated pathologies. Time-restricted feeding (TRF) is a dietary regimen in which all caloric intake is confined to a defined daily time window and has emerged as a feasible and widely adopted variant of caloric restriction.

This study investigates the effects of inactive phase TRF on skeletal muscle health in a middle-aged murine model, with a particular focus on its potential to delay or attenuate the decrease of physical performance only by modifying daily feeding schedules. Our findings demonstrate that inactive phase TRF allows to dissect the impact of mistimed nutrient intake and confers beneficial effects on skeletal muscle, including improved muscle strength and maintenance of basal glycemia during early aging. These effects were accompanied by a tendency to increase succinate dehydrogenase expression and significantly reduced lipid droplet accumulation. These effects correlate with muscle type-specific adaptations of the mitochondrial network and sarcoplasmic reticulum-mitochondria interaction in response to TRF.

Collectively, these findings support the potential of inactive phase TRF as an easy-to-follow therapeutic intervention during middle age to maintain physical performance in early aging.

Link: https://doi.org/10.1038/s41598-026-60902-2

Aging clocks of many varieties have been produced in recent years by applying machine learning techniques to a wide range of biological data that changes with age. This approach yields a tool that is disconnected from our understanding of the mechanisms of aging; links between the forms of cell and tissue damage and dysfunction that drive aging and the measures making up the clocks have yet to be determined. This makes it hard to interpret results, and hard to make practical use of a clock to assess the quality of any given approach to slowing or reversing aging. We have no idea in advance as to whether a given clock will perform well for a given intervention, and finding out is a slow process. The primary approach to this challenge taken by the research community is to produce new clocks at a fair pace, and gather as much data as possible on how the clocks behave, in search of patterns of clock behavior.

The outcome most often used to develop aging biomarkers is age itself, i.e. years lived since birth. However, in humans, relying on years lived as an outcome introduces a range of biases, most prominently confounding of aging with survival; humans in their 70s and beyond are, by definition, successful agers, having outlived most of their peers. The results of machine learning analysis differentiating older from younger people could therefore reflect not only aging-related biological damage, but also resilience.

An alternative approach that may overcome this limitation is to apply machine learning to an outcome that represents something closer to what many interventions aim to modify: the current rate of aging-related biological deterioration. We developed such a measure, Pace of Aging, by modeling changes over 20 years of follow-up in a panel of organ-function measurements among participants in the Dunedin Longitudinal Study. Critically, it also proved sensitive to the effects of calorie restriction, the intervention best established to slow aging in a range of laboratory models.

If using Pace of Aging in machine learning analysis to develop aging biomarkers can yield more sensitive endpoints for clinical trials, this would be consequential for the field. However, there are alternative explanations for the calorie restriction trial result. The participants in the trial (CALERIE) were healthy midlife adults, similar to the Dunedin Study members whose data were used to develop DunedinPACE. In contrast, the leading survival-time biomarker, the GrimAge epigenetic clock, was developed using data from older adults, many of whom had prevalent chronic disease. The critical factor could therefore be similarities between the participants whose data were used to develop the biomarker and the participants in the clinical trial.

To adjudicate between these competing hypotheses, biomarker design vs. demographic similarity, we developed a novel Pace of Aging biomarker in the same older-adult cohort used to develop GrimAge and tested its response to intervention in the CALERIE trial. We obtained data from the Framingham Heart Study Offspring Cohort. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort. When applied in independent cohorts, this novel biomarker (1) demonstrated exceptional technical reliability; (2) revealed a pattern of accelerating Pace of Aging with advancing age, replicating a finding first observed for our original Pace of Aging biomarkers developed in the Dunedin Study. In analysis of a randomized controlled trial of calorie restriction in healthy, non-obese humans (CALERIE), our novel Pace of Aging biomarker was slowed by calorie restriction, parallel to our original Pace of Aging biomarker.

Link: https://doi.org/10.64898/2026.07.07.26357388