The study drew on 321 men from the MACS/WIHS Combined Cohort Study, one of the longest-running observational research programs on HIV in the United States. Roughly 65 percent of the participants were living with HIV, and the group’s median age was 62 years. Using high-resolution B-mode ultrasound, the investigators examined each participant’s carotid arteries, the large vessels that carry blood to the brain, and looked for plaque buildup with an arterial wall thickness exceeding 1.5 millimeters, the standard marker of subclinical atherosclerosis, meaning artery disease that has not yet caused symptoms. Just under a third of the men, 31.5 percent, had detectable carotid plaque.

What makes the study methodologically striking is its layered design. The researchers first measured 14 serum sex hormones along with sex hormone-binding globulin, or SHBG, the glycoprotein that binds sex steroids in the bloodstream and regulates how much free, biologically active hormone circulates in the body. Then, in a subset of 312 men, they profiled 986 plasma metabolites using liquid chromatography-tandem mass spectrometry, a technique that separates and identifies small molecules with high precision, and quantified 2,883 plasma proteins on the Olink Explore 3072 platform, an affinity-based proteomics assay that measures proteins across inflammatory, metabolic, and cardiovascular pathways. Stool samples underwent metagenomic sequencing, allowing the team to identify gut microbial species and their relative abundances.

The central question was whether sex hormones relate to artery plaque differently in men with HIV compared with men without it, and whether the molecular fingerprints of those hormones might explain the connection. The team built what they call omics scores: linear combinations of the gut microbial species, metabolites, and proteins most strongly associated with a given hormone. If a hormone’s downstream molecular signature is also linked to plaque, that signature offers clues about mechanism, not just correlation.

The headline result concerned SHBG. In men with HIV, each one-standard-deviation increase in SHBG was associated with 40 percent lower odds of carotid plaque, with an odds ratio of 0.60 and a 95 percent confidence interval of 0.41 to 0.90. No such protective association appeared in the men without HIV, and the pattern of associations for the other sex hormones diverged between the two groups as well, hinting that HIV itself, or its long-term interplay with antiretroviral therapy and chronic immune activation, alters how the endocrine system relates to vascular health.

The multi-omics layer then revealed what SHBG is traveling with. Higher SHBG levels tracked with a measurably different overall gut microbial composition, including lower abundance of species from the genera Prevotella, Fibrobacter, and Coprococcus. They also tracked with higher levels of certain circulating metabolites, predominantly lipids and carnitine-related compounds, molecules that sit at the intersection of fat transport and mitochondrial energy metabolism, and with a protein profile enriched in the cell-cell adhesion pathway, the molecular machinery that governs how immune cells stick to blood vessel walls, a key early step in plaque formation.

Crucially, several of the individual molecules associated with SHBG were themselves associated with plaque in men with HIV. The microbial species Mediterranea massiliensis, phosphatidylcholine-based lipids, and proteins involved in immune response pathways all appeared in both lists, connecting SHBG to artery disease through three independent biological domains. When the researchers consolidated this signal into the three omics scores, the results converged: all three scores were inter-correlated with one another and each was inversely associated with carotid plaque in men with HIV. A species score, a metabolite score, and a protein score, built from completely different measurement technologies, all pointing the same direction.

The contrast group told a different story. Among men without HIV, the only significant hormone-plaque link was estrone-sulfate, a sulfated form of estrogen, which was positively associated with plaque, with an odds ratio of 3.80 and a 95 percent confidence interval of 1.41 to 10.22. Notably, estrone-sulfate showed no associations with any gut microbial species, metabolites, or proteins, suggesting its relationship to artery disease may run through a different mechanism, or that the study lacked the statistical power to detect one. This asymmetry between the two groups is one of the paper’s most provocative implications: the cardiovascular meaning of a given hormone appears to depend on HIV status.

The findings carry real-world weight because people living with HIV face an elevated burden of cardiovascular disease that traditional risk calculators do not fully capture. Even with viral suppression maintained by antiretroviral therapy, chronic inflammation, immune dysregulation, and metabolic changes persist, and heart attacks and strokes occur more often than expected. If SHBG, a molecule that can be measured cheaply in serum, genuinely marks, or perhaps mediates, a protective vascular state in this population, it could become part of risk stratification and eventually a therapeutic target.

The word “perhaps” matters here. This is a cross-sectional observational study: hormones and omics profiles and plaque were measured at the same time, so the data cannot prove that high SHBG causes less plaque. Reverse causation is plausible, since systemic illness, inflammation, and metabolic dysfunction are known to lower SHBG levels, meaning that plaque itself could conceivably drag the protein down. The authors’ exploratory mediation analyses, testing whether the omics scores statistically explain the SHBG-plaque association, are suggestive rather than definitive. Longitudinal follow-up, and ideally interventions that raise SHBG, would be needed to establish causality.

Still, the study exemplifies where cardiovascular research is heading. Rather than testing a single biomarker against a single outcome, the multi-omics approach maps the shadow a molecule casts across the gut microbiome, the metabolome, and the proteome, then checks whether those shadows fall on disease itself. SHBG, often treated as a passive transport protein, emerges from this analysis as a hub connected to gut ecology, lipid metabolism, carnitine handling, and vascular immune biology. Whether the protective signal holds over time, and whether it extends to women with HIV and other populations, will be the natural next questions. For now, the study offers men living with HIV a new molecular clue to a persistent clinical puzzle: why their arteries age faster than their calendar risk factors predict.

The SPRINTT trial, funded by the European Union’s Horizon 2020 program, was one of the largest randomized controlled trials ever conducted in community-dwelling frail older Europeans. It enrolled more than 1,500 men and women aged seventy and above across multiple European countries, all of whom met criteria for physical frailty and sarcopenia — a combination characterized by slowness, weakness, low physical activity and reduced muscle mass. Participants were randomized to either a moderate-intensity, multicomponent physical activity program, centered on walking and adapted to individual capacity, or to a control group receiving structured health education. The primary goal was to prevent major mobility disability, defined as the inability to walk 400 meters, a threshold with proven clinical relevance because it captures the capacity to function independently in everyday life. Earlier reports from the trial indicated that the intervention produced statistically significant but modest benefits, leaving open the crucial question of whether particular subgroups of patients benefited more than others.

The new study addresses that question through the lens of multimorbidity patterns rather than simple disease counts. Most previous analyses treated multimorbidity as a number — two diseases, three diseases, four or more — or as a crude index of cumulative burden. But clinicians have long observed that a patient with diabetes, peripheral vascular disease and osteoarthritis is not clinically equivalent to a patient with chronic obstructive pulmonary disease, heart failure and depression, even if both carry the same number of diagnoses. The researchers therefore applied statistical clustering techniques to the participants’ disease profiles, identifying groups of conditions that tended to occur together and grouping individuals according to the characteristic pattern of their chronic illnesses. This approach, sometimes described as person-centered rather than disease-centered, allowed the team to ask whether the protective effect of exercise against mobility loss was homogeneous across these clinically distinct constellations of disease.

The technical rationale for such heterogeneity is compelling. Different disease clusters disable the body through different physiological pathways. Cardiometabolic patterns, typically combining type 2 diabetes, hypertension and obesity, limit mobility largely through vascular damage, impaired muscle perfusion and peripheral neuropathy, all of which erode the capacity for sustained aerobic effort. Osteoarticular patterns, dominated by osteoarthritis and chronic pain, restrict movement through mechanical limitation and pain-avoidance behavior that accelerates deconditioning. Cardiorespiratory and neuropsychiatric patterns act through reduced aerobic reserve, breathlessness and fatigue, and through the motivational deficits associated with depression. A walking-based intervention that increases daily physical activity might, in principle, counteract deconditioning in all of these groups, but the magnitude of the achievable gain could differ substantially depending on which bottleneck — vascular, mechanical, respiratory or psychological — dominates the individual patient’s trajectory.

The analysis confirmed that suspicion in a clinically meaningful way. The benefits of the multicomponent physical activity program on the risk of developing major mobility disability were not uniform across multimorbidity patterns. For some clusters of conditions, the intervention produced clear and robust protection: frail older adults whose chronic disease burden followed certain patterns experienced a significantly lower hazard of losing the ability to walk 400 meters when they exercised regularly compared with their counterparts receiving health education alone. For other patterns, the observed benefit was attenuated and statistically uncertain, suggesting that standard exercise prescriptions may need to be adapted — or supplemented with other treatments — to reach patients whose disabling pathway is driven by disease mechanisms that physical activity alone cannot fully offset. The precise estimates, hazard ratios and interaction terms reported in the article quantify this differential effect, providing effect-size benchmarks that guideline developers and trial designers can build upon.

Methodologically, the study is a careful exercise in post-hoc subgroup science, a field notorious for false positives. The authors handled the inherent risks by defining multimorbidity patterns using prespecified statistical procedures, applying clustering algorithms to baseline disease data, testing interactions between intervention assignment and pattern membership, and adjusting for the covariates that typically confound mobility outcomes, including age, sex, baseline physical performance, body mass index and gait speed. Sensitivity analyses examined whether the results were robust to alternative cluster definitions and to variations in the handling of missing data. Although the analysis was not powered a priori for pattern-specific comparisons — a limitation the authors acknowledge — the coherence of the findings across analytic choices lends credibility to the central conclusion: multimorbidity is not a monolith, and its internal structure matters for prevention.

The implications reach well beyond the walls of geriatric medicine. Health systems across Europe, North America and Asia are confronting a demographic transition in which the majority of people over sixty-five live with at least two chronic conditions. Current guidelines for these patients are typically assembled disease by disease — a cardiology recommendation, a diabetes recommendation, an orthopedic recommendation — with little attention to how the combination of conditions changes what prevention can achieve. The SPRINTT analysis provides an empirical basis for a different model, one in which the pattern of multimorbidity becomes a stratification variable in clinical decision-making. A physical activity prescription for a frail older patient with a cardiometabolic cluster may be among the most effective interventions available; for a patient whose mobility is limited by a different cluster, the same prescription may need reinforcement with pain management, nutritional support, depression treatment or assistive technology to translate into preserved walking ability.

The findings also intersect with a growing body of research on physical resilience — the capacity of an organism to resist and recover from health stressors. Frailty, understood as a state of diminished physiological reserve, has often been treated as a single construct measured with composite scores such as the frailty phenotype or the frailty index. The SPRINTT results suggest that the trajectory of frail older adults is better predicted by a vector than by a scalar: the direction of their disease burden, not merely its magnitude, determines how plastic their mobility remains. This resonates with mechanistic work on the biology of aging, in which distinct molecular hallmarks — chronic inflammation, mitochondrial dysfunction, cellular senescence, neuromuscular junction degeneration — are differentially engaged by different chronic diseases and may respond differently to exercise as a systemic intervention. Physical activity is one of the few therapies known to act simultaneously on most of these pathways, which helps explain why it remains effective, if unevenly so, across clinically diverse populations.

Questions inevitably remain. The trial population consisted of community-dwelling Europeans selected for physical frailty and sarcopenia, so the generalizability of the pattern-specific results to frailer institutionalized populations, to non-European cohorts or to younger adults with early multimorbidity has not been demonstrated. The clustering solution chosen by the investigators is one of several statistically defensible partitions of the disease space, and alternative algorithms might yield patterns with different boundaries. And although major mobility disability is a validated and consequential endpoint, future work should examine whether multimorbidity patterns also moderate the effects of exercise on other outcomes, including falls, hospitalization, cognitive decline and mortality. Longer follow-up, larger samples and replication in independent cohorts will be needed before pattern-stratified exercise prescriptions become standard clinical practice.

Even with those caveats, the study marks a turning point in how the prevention of disability in old age can be conceptualized. It moves the field away from the blunt arithmetic of disease counting and toward a nosology of combinations, in which the specific constellation of conditions a person carries is treated as clinically actionable information. It also delivers a pragmatic message of hope with nuance: exercise remains one of the most powerful tools available for keeping frail older adults on their feet, but its power is conditional, and understanding those conditions is the key to unlocking it for everyone. As populations age and multimorbidity becomes the norm rather than the exception, the lesson from SPRINTT is that precision geriatrics — matching preventive interventions to the pattern of disease, not just to its burden — is no longer an aspiration but an evidence-backed necessity.

The review, led by Jim Jacob and Federica Sarno of the University of Groningen’s University Medical Center Groningen, together with Maria Zernova, Inge M. Strating, Barbara van Munster, and Monika Trzpis, set out to answer a deceptively simple question. If delirium arises from an interaction between predisposing vulnerabilities—advanced age, neurodegeneration, frailty—and acute precipitating factors such as inflammation, surgery, or critical illness, could methylation changes be part of the molecular wiring that connects the two? The team systematically screened the literature and identified 1,110 potentially relevant articles. After applying their inclusion criteria, only nine studies survived. That attrition alone tells a story: despite a strong theoretical rationale, the empirical record linking DNA methylation to delirium is thin, and the authors conclude that robust evidence remains lacking.

The nine included studies split into two broad families. Six examined differential DNA methylation at candidate CpG sites—the cytosine–guanine dinucleotides where methyl groups are most commonly attached and where methylation is known to influence transcription. Three took a different tack, assessing age-related methylation patterns stratified by delirium status, exploiting the fact that the methylation state of many sites across the genome shifts predictably with chronological and biological age. Only four of the nine studies performed true genome-wide differential methylation analysis, the kind of unbiased survey that can, in principle, discover methylation signatures no one thought to look for in advance. The remaining studies were hypothesis-driven, focusing on genes selected for their plausibility.

Among the four genome-wide studies, two independent investigations each identified a single CpG site that was hypomethylated in patients who experienced delirium. The first site, cg21295729, annotated to the gene LDLRAD4, was found in blood and involved a comparison of 43 delirium cases against 44 controls. The second, cg16526133, annotated to ADAMTS9, emerged in brain tissue, comparing 11 cases with 25 controls. Hypomethylation at a CpG site typically suggests increased accessibility of DNA to transcriptional machinery, hinting—though only hinting—that these genes might behave differently in people who develop the syndrome. Notably, LDLRAD4 and ADAMTS9 have no obvious shared functional storyline, and the two studies pointed to different tissues, different cohorts, and different design logic. The other two genome-wide studies found no statistically significant methylation differences at all, a result the review does not shy away from reporting.

Perhaps the most intriguing signal in the review involves inflammation. Gene-specific analyses showed that methylation levels at CpG sites annotated to the TNF gene—the canonical inflammatory cytokine tumor necrosis factor—correlated negatively with age in peripheral blood mononuclear cells and in whole blood samples taken from delirious patients. In plain terms, the older the delirious patient, the lower the methylation at these TNF-associated sites, a pattern consistent with progressively disinhibited inflammatory gene expression in a vulnerable host. Critically, this age-dependent pattern was absent in saliva and buccal samples, and absent in control subjects. That tissue specificity matters enormously. It suggests that the association is not a generic artifact of aging, but something particular to blood-derived immune cells in patients who actually went through a delirious episode. Blood, of course, carries the immune cells believed to orchestrate the systemic inflammatory response that many theories place at the center of delirium pathophysiology.

A complementary pattern emerged for genes involved in neurotrophic signaling. CpG sites annotated to BDNF, GDNF, and NR4A2—genes encoding factors that support neuronal survival, plasticity, and synaptic resilience—showed a positive correlation with age in delirious patients, meaning methylation increased as patients got older. Because increased promoter methylation is often, though not invariably, associated with reduced gene expression, the finding raises the possibility of an age-related epigenetic tightening of the brain’s own maintenance systems. In a patient facing an acute inflammatory or metabolic insult, the combination of a revved-up immune program and a dampened neurotrophic program is precisely the kind of double hit that theories of delirium have long hypothesized: the brain, already running on diminished reserves, is simultaneously provoked and deprived of support at the moment of the insult.

The reviewers are careful, and admirably so, about what such signals can and cannot support. Methylation measured in blood may or may not reflect what is happening in neurons or glia; the brain-tissue study was small, with just 11 cases; and methylation is highly sensitive to cell-type composition, meaning that shifts in the proportions of immune cell subsets could masquerade as differential methylation. The studies also varied widely in sample size, tissue type, statistical thresholds, and whether analyses corrected for the many confounders—age, medication, illness severity, smoking, diet—that are known to sculpt the methylome. Two of the four genome-wide studies reported nothing significant, and the authors emphasize that the existing literature is limited both in number and in methodological rigor, constraining firm conclusions about whether methylation is a cause, a consequence, or merely a correlate of the syndrome.

What makes the field worth watching is the underlying biology. DNA methylation is a dynamic layer of regulation; while many marks are stable, others respond within hours or days to inflammation, hypoxia, and stress hormones, all of which surge during the kinds of acute events that precipitate delirium. Methylation also offers something epidemiology alone cannot: a mechanistic bridge between vulnerability and insult. If older brains carry methylation signatures that favor TNF derepression in immune cells while simultaneously suppressing neurotrophic support, then a surgical trigger or a fever could plausibly flip a network of gene-expression switches that cumulatively destabilize cognitive control circuits. The convergence of the two methylation trends—one pointing toward immune activation, the other toward weakened neuronal maintenance—is conceptually coherent with prevailing models of delirium, even if the empirical evidence has not yet reached the strength that coherence deserves.

The practical implications of the review are correspondingly modest but clear. The authors argue that what the field needs is larger, well-powered, longitudinal cohort studies with genome-wide methylation profiling, careful adjustment for confounders, and ideally paired blood and brain tissue to test whether peripheral signals mirror central ones. Prospective designs, in which methylation is measured before surgery or before an infection takes hold, would help distinguish pre-existing epigenetic vulnerability from methylation changes induced by the episode itself. Standardized covariate adjustment and cell-composition correction would strengthen comparability across studies. Until then, the review stands as both a map and a warning: DNA methylation remains a theoretically compelling contributor to delirium pathophysiology, supported by a handful of suggestive and partially converging findings, but the field has yet to produce the rigorous, replicated evidence required to elevate epigenetics from plausible mechanism to established biology. For clinicians and researchers watching a rapidly aging global population, closing that evidence gap is not an academic luxury; it is the necessary groundwork for the first epigenetically informed approaches to predicting, and perhaps one day preventing, one of medicine’s most disruptive syndromes.

To appreciate why methylation has drawn attention in delirium research, it helps to understand how plastic this mark can be. Cytosine methylation is maintained by enzymes of the DNMT family and actively removed through TET-mediated oxidation pathways, creating a reversible system that responds to environmental and physiological cues. In the immune system, stimulus-responsive methylation changes are well documented: monocytes and T cells remodeled their methylomes within hours of activation, and inflammatory cytokine promoters are among the genomic regions most sensitive to such remodeling. This makes blood an attractive, if imperfect, surrogate tissue for studying the interface between systemic inflammation and brain dysfunction.

Age adds a second layer of complexity. Large consortium analyses of thousands of blood and brain samples have shown that methylation drifts in a highly stereotyped way across the lifespan, and that some loci accelerate or decelerate their drift in the context of disease. The delirium studies reviewed here sit squarely within this tradition, testing whether the syndrome modifies the expected age-methylation relationship rather than producing absolute differences between cases and controls. That analytic framing may be well suited to a condition defined by interactions between age-related vulnerability and acute insult, though it also demands large, age-diverse samples that most existing cohorts cannot provide.

The review also reflects a broader methodological moment. Epigenome-wide association studies in neuropsychiatry have repeatedly shown that small cohorts underpowered to detect the modest effect sizes typical of methylation differences. The field’s experience elsewhere suggests that combining cohorts, harmonizing platforms, and sharing raw data will be prerequisites for any credible replication of the signals highlighted in this work.

Subject of Research: DNA methylation as a candidate molecular mechanism in delirium pathophysiology

Article Title: A systematic review on the contribution of DNA methylation to delirium pathophysiology

Article References: Jacob, J., Zernova, M., Strating, I. M., van Munster, B., Sarno, F., & Trzpis, M. (2026). A systematic review on the contribution of DNA methylation to delirium pathophysiology. Epigenetics Communications. https://doi.org/10.1186/s43682-026-00051-9

Image Credits: AI Generated

DOI: 10.1186/s43682-026-00051-9

Keywords: delirium, DNA methylation, epigenetics, systematic review, TNF, inflammation, aging, neurotrophic signaling, BDNF, genome-wide methylation, neuropsychiatry, blood-based biomarkers

Intrinsic capacity is a concept that has steadily gained traction in gerontology since the World Health Organization’s Decade of Healthy Ageing placed it at the center of its global strategy. Rather than viewing aging through the narrow lens of disease, intrinsic capacity assembles all of a person’s physical and mental capacities into a single multidimensional construct. In this study, the researchers operationalized it across five distinct domains: mobility, cognition, psychological well-being, sensory function, and vitality. Each domain captures a facet of what an older adult can actually do in daily life, from walking and gripping to remembering, seeing, hearing, maintaining nutrition, and sustaining emotional equilibrium. The central question was deceptively simple: which of these domains matter most when it comes to how older Europeans evaluate their own quality of life, and do those relationships hold equally for men and women, and across the continent’s north-south and east-west divides?

To answer it, the team analyzed longitudinal data from 11,493 adults aged 50 and older who participated in SHARE Waves 5 and 6, covering the years 2013 to 2015. Quality of life was measured using the CASP-12 scale, a validated instrument that assesses four core dimensions of self-reported well-being in later life: control, autonomy, self-realization, and pleasure. The researchers first employed exploratory factor analysis to confirm that the five intrinsic capacity domains genuinely cluster together as a coherent multidimensional construct rather than behaving as isolated traits. They then turned to network analysis, a statistical technique that maps the web of interconnections among variables, to examine how the domains relate to one another and to quality of life, before stratifying results by sex and region to expose hidden disparities.

The statistical architecture of the study is worth appreciating because it reflects a broader shift in how aging research is conducted. Factor analysis served as a gatekeeper, validating that the underlying structure of intrinsic capacity behaved as theorized. Network analysis then went beyond traditional regression by revealing the direct edges between individual indicators and the CASP-12 score, allowing the team to see, for example, that depressive symptoms measured by the European Depression Scale correlated negatively with quality of life at a coefficient of −0.284, while fatigue correlated at −0.324, both highly significant at p below 0.001. These two indicators, nested within the psychological and vitality domains respectively, emerged as the strongest negative correlates of quality of life in the entire network. Cognitive performance and mobility showed weaker but still significant associations, while sensory function played a comparatively modest role.

Over the two-year window between survey waves, the researchers observed a pattern that is both sobering and unsurprising: modest declines in intrinsic capacity paralleled measurable changes in quality of life. The trajectory is important precisely because it is longitudinal. Cross-sectional studies can only show that capacity and well-being travel together at a single moment, leaving open the question of direction. By tracking the same individuals across time, this analysis strengthens the case that deterioration in intrinsic capacity contributes to declining quality of life, and conversely, that preserving capacity may buffer well-being against the inevitable erosion of age. For geriatricians and public health planners, that temporal link is the difference between a correlation worth noting and a lever worth pulling.

Perhaps the most consequential findings concern who bears the greatest burden. Women in the sample exhibited greater deficits in intrinsic capacity and lower quality of life than men, a result consistent with a substantial body of literature documenting the compounding disadvantages that accrue to women over the life course, from higher rates of chronic disease and disability to steeper trajectories of depressive symptoms in old age. Just as striking were the regional patterns. Older adults living in Southern and Eastern Europe showed greater capacity deficits and lower quality of life than their counterparts elsewhere on the continent. The study did not disentangle the full causal web behind these geographic gradients, but the authors frame them within the broader literature on social determinants of health, pointing to differences in income security, health care access, social protection systems, and living arrangements that vary systematically across European welfare regimes.

The regional divide deserves particular scrutiny because it transforms a psychological finding into a political one. If fatigue and depressive symptoms are the strongest correlates of poor quality of life, and if those symptoms cluster disproportionately in regions with weaker social safety nets, then the implication is that mood and energy in old age are not merely private experiences but barometers of policy environments. Pension adequacy, access to mental health services for older adults, community-based support structures, and the availability of preventive care all shape the daily conditions under which intrinsic capacity is maintained or lost. The authors argue explicitly that addressing sex and regional disparities in intrinsic capacity could improve well-being and reduce inequalities across aging populations, an argument that lands with force as European demographics tilt steadily older. Across the continent, the share of people over 65 continues to climb, and the sustainability of health systems will depend increasingly on keeping older adults capable and engaged rather than merely alive.

From an intervention standpoint, the identification of psychological well-being and mobility as priority domains is a call to sharpen existing tools. Depression in later life is chronically underdiagnosed and undertreated, partly because its presentation is often mistaken for a normal feature of aging or masked by physical complaints. The study’s finding that depressive symptoms carry one of the strongest negative associations with quality of life suggests that screening for mood disorders in primary care settings serving older adults, and integrating psychological support into standard geriatric assessment, could yield benefits disproportionate to their cost. Similarly, mobility interventions, from structured physical activity programs to environmental modifications that reduce fall risk and preserve independence, align directly with the second key domain. Fatigue, the single strongest negative correlate at −0.324, is more elusive, but it frequently flags underlying nutritional deficits, anemia, sleep disturbance, or sedentary deconditioning, all of which are modifiable when detected early.

The study is not without limitations, and the authors are careful about the scope of their claims. The data derive from self-reported instruments and span a comparatively short two-year period, and the analysis of secondary data precludes the experimental control needed to establish definitive causation. Yet the sheer scale and geographic breadth of SHARE, together with the methodological rigor of combining factor analysis, network analysis, and stratified comparisons, gives the findings a weight that smaller, single-country studies cannot match. What emerges is a clear and actionable picture of aging in Europe: intrinsic capacity functions as an integrated system whose psychological and mobility components anchor its connection to quality of life, women and residents of Southern and Eastern Europe face systematic disadvantages that demand targeted policy attention, and even modest preservation of capacity over short horizons tracks with better lived experience. As the World Health Organization’s Decade of Healthy Ageing presses toward 2030, this research supplies precisely the kind of evidence needed to move the healthy aging agenda from aspiration to measurement, and from measurement to intervention.

The choice of SHARE as the data backbone of the study merits a brief note for readers unfamiliar with the infrastructure behind such findings. SHARE is a panel survey that interviews the same households repeatedly, harmonizing questions across participating countries so that measures of health, cognition, and economic circumstances remain comparable from Sweden to Spain. That harmonization is what makes a stratified comparison of Northern and Southern Europe statistically meaningful rather than anecdotal, and it explains why the dataset has become a standard resource for cross-national aging research since its first wave in 2004.

The CASP-12 instrument also deserves attention, because it shapes what the study can and cannot say about well-being. Unlike satisfaction measures that ask people to evaluate their lives against a standard, CASP-12 probes whether respondents feel they control their own lives, can act autonomously, pursue self-realization, and experience pleasure. This orientation means the scale is sensitive to the everyday capacities that intrinsic capacity frameworks aim to capture, which may partly explain why psychological and mobility indicators register such clear associations with the score.

The network-analytic approach used by the authors reflects a methodological trend worth understanding. Rather than treating latent constructs as causes of observed symptoms, network models depict symptoms and capacities as mutually reinforcing elements of a system. In such a view, fatigue can erode activity, reduced activity can deepen low mood, and low mood can further drain energy, creating feedback loops that a single regression coefficient would obscure. The correlations reported here, such as the negative links between depressive symptoms and quality of life, are best read as edges in that system rather than isolated effects.

Finally, the two-year horizon of the analysis is both a strength and a boundary on interpretation. Short intervals capture change before cohort effects and survivorship distort the sample, yet they cannot speak to how capacity and quality of life co-evolve over decades. Longer panel follow-up will be needed to test whether early deficits in psychological well-being foreshadow steeper declines later in life.

Subject of Research: The relationship between intrinsic capacity domains and two-year changes in quality of life among older Europeans, including sex and regional differences, analyzed using SHARE data

Article Title: Intrinsic capacity and changes in quality of life among older Europeans by sex and region using SHARE data

Article References: Llorens-Ortega, R., Bertran-Noguer, C., Juvinyà-Canal, D., Garre-Olmo, J., & Bosch-Farré, C. (2026). Intrinsic capacity and changes in quality of life among older Europeans by sex and region using SHARE data. Discover Social Science and Health. https://doi.org/10.1007/s44155-026-00484-6

Image Credits: AI Generated

DOI: 10.1007/s44155-026-00484-6

Keywords: intrinsic capacity, quality of life, aging, older adults, SHARE, sex differences, regional disparities, depressive symptoms, mobility, CASP-12, healthy aging, Europe

The distinction matters because people of the same chronological age can have radically different physiological capacities. One 85-year-old may live independently, remain physically active and have little cognitive impairment, while another may already require help with daily activities, have substantial muscle loss, multiple chronic illnesses and limited social support. These differences influence how the body responds to infection, surgery, respiratory failure or circulatory shock, and how effectively it can rebuild damaged tissues afterward. Chronological age captures the passage of time, but it does not directly measure organ-system reserve, immune resilience, nutritional status, cognition or functional independence. The authors therefore emphasize that age alone should not be used either to deny intensive care to a robust older person or to justify aggressive treatment when the prospect of meaningful recovery is very low.

Frailty is presented as the most useful starting point for understanding this variation. Clinically, frailty describes a state of increased vulnerability produced by the cumulative decline of several physiological systems. A frail person may have less muscle strength, slower movement, reduced energy, impaired balance, diminished nutritional reserves and less ability to compensate when illness disrupts normal body functions. In intensive care, that vulnerability can be amplified by immobilization, inflammation, sedation, invasive procedures and prolonged organ support. Frailty is associated with higher risks of death, functional deterioration, institutionalization and reduced quality of life, but the article cautions against treating it as a single numerical verdict. Instead, it should prompt a broader assessment of functional status, cognition, multimorbidity, medication burden, nutrition, living circumstances and the outcomes the patient values most.

That broader assessment could change the question clinicians ask at the bedside. Rather than deciding whether a person is “too old” for intensive care, physicians should consider whether intensive treatment is likely to produce an outcome compatible with the individual’s goals. For a robust older adult, a difficult ICU admission followed by rehabilitation and a return home may be an acceptable trade-off. For a person with advanced frailty, severe cognitive impairment and profound dependence, the burdens of prolonged ventilation, dialysis or repeated invasive procedures may outweigh the chance of achieving an acceptable recovery. Neither conclusion can be reached from age alone. Frailty-informed medicine is intended to prevent two opposite errors: therapeutic nihilism, in which potentially beneficial treatment is withheld from older adults, and the continuation of burdensome, non-beneficial treatment when the likely outcome conflicts with the patient’s wishes.

The authors place shared decision-making at the center of this revised framework. Intensive-care choices are often made during rapidly evolving emergencies, when prognosis is uncertain and patients may be unable to communicate. Whenever possible, older adults should participate directly in decisions about ICU admission, escalation of treatment, continuation of life-sustaining therapies and rehabilitation. Advance care planning and advance directives can provide crucial information about what kinds of survival, disability or dependence a person would accept. When a patient lacks decision-making capacity, relatives and legally recognized surrogates should not be asked merely to choose between technical procedures. Their role is to help clinicians reconstruct the patient’s values, priorities and previously expressed preferences, including how the patient weighed survival against independence, cognition, comfort and quality of life.

This communication should continue beyond the initial emergency. A decision made at ICU admission may need to be revisited as the patient’s condition evolves, new information becomes available or the burdens of treatment become clearer. Discussions may therefore include whether to escalate organ support, when to limit or withdraw life-sustaining interventions, what rehabilitation can realistically achieve and what type of discharge environment will be needed. The article describes transparent and compassionate communication not as an optional supplement to advanced medical technology, but as a core component of high-quality critical care. In practice, this means acknowledging uncertainty rather than offering false precision, explaining the likely benefits and burdens of treatment, and making room for changing goals as recovery—or deterioration—unfolds.

The proposed approach also breaks down the traditional division between intensive-care medicine and geriatrics. Intensivists bring expertise in acute organ failure, infection, hemodynamic instability and life-support technologies. Geriatricians contribute a detailed understanding of frailty, multimorbidity, polypharmacy, cognitive impairment, functional reserve and the long-term consequences of critical illness. Working together before ICU admission when possible, during the acute phase and after discharge could help teams balance immediate survival against longer-term function. The authors extend this call to a much larger multidisciplinary network. Nurses, physiotherapists, occupational therapists, pharmacists, nutrition specialists, psychologists, social workers, rehabilitation teams and primary-care clinicians all influence whether an older survivor regains mobility, maintains cognition, manages medications safely and returns to a meaningful social role.

A major implication is that ICU success cannot be measured adequately by survival at discharge. Mortality, hospital length of stay and ICU length of stay are convenient endpoints, but they conceal what happens after the hospital doors close. Recovery from critical illness may take months or years, and older patients can follow markedly different paths depending on their pre-existing vulnerability, the severity of the acute illness, exposure to sedation and mechanical ventilation, opportunities for rehabilitation and the resources available in their communities. Some may return to their previous level of independence; others may survive with new physical disability, cognitive problems, depression, anxiety or persistent symptoms. This cluster of consequences is often described as post-intensive care syndrome, which can affect physical, cognitive and psychological health in survivors and place substantial strain on families and caregivers.

Looking at recovery as a trajectory creates opportunities for intervention at several points. Before a planned operation or other high-risk treatment, “prehabilitation” may seek to improve strength, nutrition, exercise capacity and psychological readiness. During critical illness, strategies that reduce avoidable neurological and neuromuscular injury—such as minimizing unnecessary sedation, supporting early mobility when safe and protecting sleep and cognition—may help preserve the capacity to recover. After ICU discharge, structured rehabilitation, comprehensive geriatric assessment, intermediate-care facilities, acute geriatric wards and coordinated community follow-up may bridge the dangerous gap between hospital survival and restored independence. These measures cannot guarantee a particular outcome, but they recognize that recovery is an active biological and social process rather than an automatic consequence of surviving organ failure.

The article also insists that end-of-life care belongs within, rather than outside, geriatric critical care. Modern medicine can sustain circulation, breathing and kidney function even when the overall direction of a person’s illness is irreversible. The ability to maintain physiological functions does not by itself demonstrate that continued treatment is beneficial. Decisions to withhold or withdraw life-sustaining therapies should be based on a careful synthesis of prognosis, frailty, functional status and the patient’s preferences—not on age-based exclusion or an assumption that every available intervention must be continued. When treatment is judged non-beneficial, limiting it should be accompanied by meticulous control of pain, breathlessness, agitation and other symptoms, with palliative-care involvement when appropriate and sustained support for relatives. The emerging paradigm is therefore not simply about extending life for as long as technology permits. It is about aligning intensive care with dignity, autonomy, cognition, function, social participation and the values that make survival meaningful. The decisive question is no longer whether a very old patient can be kept alive in an ICU, but whether intensive care can help that person reach a recovery—or a peaceful final phase—that remains consistent with who they are and what they want.

The work focuses on senescent cells, sometimes described as “zombie” cells because they stop dividing but do not die. Cell division is essential during development and for repairing damaged tissues, yet cells can permanently exit the cell cycle after experiencing stress, damage or repeated replication. Senescent cells remain metabolically active and continue to communicate with their surroundings. They release a collection of inflammatory proteins, immune-signaling molecules and other factors known as the senescence-associated secretory phenotype, or SASP. As senescent cells accumulate, their secretions can create a chronic inflammatory environment associated with aging, cancer, cardiovascular disease, neurodegeneration and other disorders. Understanding why SASP remains active has therefore become a central goal in efforts to promote healthier aging.

The new study reveals that SASP is driven by the convergence of two mitochondrial pathways. One pathway changes the accessibility of DNA, making inflammatory genes easier for the cell to read. The other activates transcription factors that bind to those exposed genes and stimulate production of inflammatory molecules. “It turns out that there is a convergence of at least two biological pathways related to mitochondria,” said Peter Adams, PhD, a co-corresponding author and the Jeanne and Gary Herberger Leadership Chair in Cancer Research at Sanford Burnham Prebys. Adams is also director and professor in the institute’s Cancer Genome and Epigenetics Program. The findings suggest that senescent cells do not simply become inflammatory because of one isolated defect; instead, their metabolic and immune systems reinforce one another.

Mitochondria are best known as the organelles that generate cellular energy, but they also produce molecules that influence gene regulation. In senescent cells, the researchers found that mitochondria engaged in altered metabolism generated increased amounts of acetyl-CoA. This molecule is a central metabolic intermediate used in energy production and biosynthesis, but it can also affect chromatin, the molecular complex that packages DNA. Acetyl-CoA supplies acetyl groups to histone proteins, which act like spools around which DNA is wound. Histone acetylation generally loosens the interaction between histones and DNA, allowing regions of the genome to become more accessible to the transcriptional machinery. In this case, increased acetyl-CoA helped open chromatin near genes involved in the SASP, creating a genomic environment that favored inflammatory gene expression.

The metabolic signal alone, however, was not sufficient to keep the inflammatory program running. The team found that senescent mitochondria also become damaged and leaky, allowing fragments of mitochondrial DNA and RNA to escape into the cell. Because mitochondria evolved from ancient bacteria, their genetic material can resemble molecular patterns associated with infection. When misplaced mitochondrial nucleic acids enter the cytoplasm, they can activate innate immune sensors and inflammatory signaling pathways. These pathways turn on transcription factors that move toward the newly accessible SASP genes. The result is a two-part mechanism: acetyl-CoA changes the epigenetic landscape, while mitochondrial DNA and RNA activate the immune machinery needed to transcribe the exposed genes.

This interaction helps explain how a cell can remain in a long-lasting inflammatory state even after the original stress that caused senescence has disappeared. Epigenetic changes determine which genes are physically available for use, while immune signals determine whether the cell’s transcriptional machinery is instructed to use them. According to Adams, the researchers wanted to know whether disrupting one part of this partnership could weaken the entire SASP program. Their experiments focused on CTPI-2, a compound that blocks a transport protein involved in supplying a component required for acetyl-CoA production. By limiting this metabolic input, the researchers aimed to prevent inflammatory chromatin regions from remaining open, without directly suppressing every immune signal generated by damaged mitochondria.

In experiments involving mice, CTPI-2 reduced inflammation across multiple tissues and was associated with improved tissue function and healthspan during aging. The treatment did not eliminate the immune signaling caused by mitochondrial leakage. Instead, it interfered with the metabolic component that made SASP genes more accessible. This distinction is important because broad suppression of immune activity can leave older organisms more vulnerable to infections and impair their ability to respond to injury. A strategy that selectively reduces the inflammatory output of senescent cells, while preserving other immune functions, could offer a more precise approach. The researchers emphasize that CTPI-2 remains an experimental tool and that the findings in mice do not establish safety or effectiveness in humans.

The study was led by João Passos, PhD, professor of Physiology at Mayo Clinic, with Hélène Martini, PharmD, PhD, a postdoctoral researcher in the Passos laboratory, serving as first author. The investigators included scientists from Sanford Burnham Prebys, Mayo Clinic, Imperial College London, Albert Einstein College of Medicine and the University of Glasgow. Their results add to a growing body of research showing that metabolism and epigenetic regulation are tightly connected. Nutrient availability, mitochondrial activity and the production of metabolic intermediates can all influence chromatin structure and gene expression. In aging cells, these relationships may become distorted, allowing metabolic changes to amplify inflammatory programs that would normally be temporary or tightly controlled.

The researchers say the findings point toward a new class of potential anti-aging interventions: therapies that target metabolic signals controlling DNA accessibility rather than attempting to remove every senescent cell or block inflammation throughout the body. Such treatments could eventually be combined with senolytic drugs, which are designed to eliminate senescent cells, or with other approaches aimed at improving mitochondrial quality. Much more work is needed to determine whether the same acetyl-CoA-dependent mechanism operates in human tissues, how widely CTPI-2 affects metabolism, and whether long-term treatment produces unwanted effects. For now, the mouse results provide evidence that mitochondrial metabolism and epigenetic control form a crucial molecular bridge between cellular aging and chronic inflammation. The study’s authors argue that disrupting this bridge may help preserve tissue performance and reduce functional decline in later life.

Subject of Research: Animals

Article Title: Mitochondrial metabolism and epigenetic crosstalk drive SASP

News Publication Date: 29-Jul-2026

Web References: Nature article; Peter Adams, PhD; João Passos, PhD

References: Nature; DOI: 10.1038/s41586-026-10791-2

Image Credits: Sanford Burnham Prebys

Keywords: Aging populations, older adults, gerontology, chronic inflammation, inflammatory signaling, mitochondria, mitochondrial function, metabolism, senescence-associated secretory phenotype, acetyl-CoA, epigenetics, healthy aging

The study drew on data from the Swedish National Study on Aging and Care in Kungsholmen, known as SNAC-K. Researchers included 2,981 people who were at least 60 years old when they entered the study and followed them for as long as 15 years. To estimate eating patterns, participants reported when they typically consumed food during a 24-hour period. From this information, investigators calculated the longest interval between meals on a usual day. This measure was intended to capture habitual fasting duration rather than a short-term dietary experiment. Participants were then assessed over time for the emergence or accumulation of chronic conditions, allowing the researchers to examine whether daily meal spacing was linked to the progression of multimorbidity, the medical term for living with several chronic diseases.

The clearest contrast emerged between participants whose longest daily interval without food lasted six to 11.5 hours and those whose longest interval extended from 14 to 24 hours. Older adults in the longer-interval group accumulated chronic diseases at a faster rate. The pattern was observed when researchers considered the overall number of chronic conditions and remained apparent for cardiovascular and neuropsychiatric diseases. Cardiovascular conditions include illnesses affecting the heart and blood vessels, while neuropsychiatric disorders involve the interaction of neurological and mental health processes. The researchers did not observe the same association for musculoskeletal diseases, suggesting that meal timing may not relate equally to every category of illness.

The results are significant because fasting research has largely focused on younger and middle-aged adults, many of whom are studying fasting as a strategy for weight control, metabolic health or longevity. In those populations, time-restricted eating and intermittent fasting have produced mixed results, with some studies reporting modest improvements in body weight, blood glucose regulation or insulin sensitivity. Older adults, however, face a different biological and clinical landscape. Aging is accompanied by changes in appetite, digestion, muscle mass, kidney function and the body’s ability to respond to nutritional stress. A long interval without food may therefore have different consequences in later life, particularly for people who already eat small quantities or have difficulty maintaining weight.

One possible explanation is that prolonged gaps between meals could make it harder for older adults to consume enough energy and protein across the day. Adequate protein distribution is important for maintaining skeletal muscle, and insufficient intake can contribute to sarcopenia, the age-related loss of muscle mass and strength. Extended fasting could also affect blood glucose stability, especially in people taking medications for diabetes or other metabolic conditions. If long meal intervals are accompanied by inadequate hydration, reduced appetite or episodes of overeating later in the day, the overall pattern may become nutritionally unbalanced. These mechanisms remain hypotheses rather than conclusions from the study, but they illustrate why the effects of meal timing may depend on age, health status, medication use and total dietary intake.

The association was strongest among adults aged 78 and older. This finding may reflect the greater physiological sensitivity of the oldest participants, who are more likely to experience frailty, unintended weight loss, impaired appetite and multiple medications. It may also indicate that the same fasting duration represents a greater nutritional challenge for someone with low energy requirements but reduced ability to eat large meals. In advanced age, a missed meal can account for a substantial share of the day’s calories and protein. At the same time, the study cannot determine whether long fasting intervals directly accelerated disease accumulation or whether existing health problems caused people to eat less frequently.

That distinction is central to interpreting the findings. The research was observational, meaning that investigators measured naturally occurring eating habits rather than assigning participants to fasting schedules. People who had longer intervals between meals may have differed from those with shorter intervals in many other ways. They could have had poorer appetite, more severe disease, lower mobility, different sleep patterns or socioeconomic circumstances that affected both eating behavior and health. Some participants may also have lengthened their fasting periods because illness made eating difficult. This phenomenon, known as reverse causation, could make fasting appear to predict disease progression when underlying disease was actually influencing meal timing. Although statistical analyses can account for some factors, they cannot eliminate every source of bias in an observational study.

The researchers also relied on participants’ recollection of when they typically ate, rather than continuous measurements from food diaries, digital devices or controlled feeding studies. Self-reported information may not capture irregular meals, snacks, drinks containing calories or changes in eating patterns over the 15-year follow-up period. The longest daily interval was estimated from a reported routine, so it should not be interpreted as a precise measurement of every fasting episode. Even with these limitations, the long follow-up and detailed health data from SNAC-K provide a valuable view of how habitual meal timing may relate to aging and multimorbidity in a real-world population.

Adrián Carballo Casla, the study’s last author and a postdoctoral researcher at Karolinska Institutet’s Aging Research Center, said the findings suggest that fasting may have different associations in older adults, particularly among the oldest age groups. The message is not that every older person should eat more frequently or that fasting is inherently dangerous. Instead, the study points to the importance of individualized nutritional advice. For an older adult who is healthy, maintains body weight and consumes sufficient nutrients, a particular eating schedule may be well tolerated. For someone experiencing frailty, diabetes, unintentional weight loss or multiple chronic conditions, long gaps between meals may require closer medical and dietary supervision.

The study adds a timely caution to the rapidly expanding conversation around intermittent fasting and longevity. Meal timing is only one part of nutrition, and the quality, quantity and distribution of food may be more important than the fasting window alone. Future research will need to test specific eating schedules in randomized clinical trials involving older adults and measure outcomes such as muscle strength, nutritional status, blood glucose, cardiovascular health and cognitive function. Until those studies are available, the new evidence supports a careful approach: fasting strategies developed for younger populations should not automatically be assumed to benefit people in later life, especially those aged 78 and above or those already living with several chronic diseases.

Subject of Research: People, particularly older adults aged 60 years and older

Article Title: “Habitual fasting duration and accelerated multimorbidity in older adults”

News Publication Date: 20-Aug-2026

Web References: https://doi.org/10.1111/joim.70150

References: Luis Kalmbach, David Abbad-Gomez, Giorgi Beridze, Fernando Rodríguez-Artalejo, Davide Liborio Vetrano, Amaia Calderón-Larrañaga and Adrián Carballo-Casla, “Habitual fasting duration and accelerated multimorbidity in older adults,” Journal of Internal Medicine, published online August 20, 2026. DOI: 10.1111/joim.70150

Image Credits: Photo: Maria Yohuang. Image of Adrián Carballo Casla.

Keywords: older adults, fasting, meal timing, intermittent fasting, multimorbidity, chronic diseases, cardiovascular disease, neuropsychiatric disease, aging, nutrition, Karolinska Institutet, observational study

XPRIZE Healthspan is a seven-year competition designed to push aging research beyond incremental improvements. Participating teams are developing and testing interventions intended to restore muscle, cognitive, and immune performance in adults between 50 and 90 years of age. The competition defines success as producing measurable improvements equivalent to at least 10 years of healthier function—and potentially as much as 20 years—within one year or less of treatment. The goal is not simply to increase lifespan, but to delay or reverse functional decline while people remain active and independent.

The NYC-Vita team is conducting a clinical trial that combines lifestyle and pharmaceutical interventions to examine whether immune-system performance can be improved during aging. The study reflects a growing scientific consensus that aging is not governed by a single mechanism. Instead, it emerges from interconnected changes involving chronic inflammation, metabolic dysfunction, impaired tissue repair, altered immune-cell behavior, vascular damage, and declining neurological resilience. By measuring these processes together, the researchers hope to determine whether targeted interventions can produce broad improvements in healthspan rather than isolated changes in one organ.

A central scientific focus of the program is the aging immune system, a process known as immunosenescence. With age, immune cells may become less responsive to new infections and vaccines, while other immune populations can remain persistently activated and promote low-grade inflammation. This chronic inflammatory state, sometimes called inflammaging, has been associated with cardiovascular disease, neurodegeneration, frailty, metabolic disorders, and reduced ability to recover from illness. NYC-Vita is designed to investigate whether pharmaceutical and behavioral strategies can shift the immune system toward a more balanced and effective state.

The Mount Sinai effort brings together specialists in immunology, neuroscience, metabolism, medical imaging, wearable technology, and clinical investigation. Miriam Merad, MD, PhD, leads the NYC-Vita team and is internationally recognized for her research on macrophages, immune cells that regulate inflammation, tissue repair, and responses to disease. The team also includes Zahi Fayad, PhD, whose work uses advanced imaging and wearable technologies to study biological and lifestyle stressors; Fanny Elahi, MD, PhD, an expert in neurodegeneration and brain health; Thomas Marron, MD, PhD, principal investigator of the NYC-Vita clinical trial; and Ryan W. Walker, PhD, MS, whose research examines metabolic and nutritional influences on healthy aging.

For the study, the researchers are expected to evaluate healthspan using multiple biological and functional measures rather than relying on chronological age alone. Such assessments can include immune-cell profiles, inflammatory markers, metabolic measurements, neurocognitive testing, physical-performance data, and imaging-based indicators of tissue health. Wearable devices may provide continuous information about activity, sleep, heart-rate patterns, and other behavioral signals. Combining these data streams could help researchers identify whether an intervention produces a coordinated improvement across systems or merely changes a laboratory measurement without meaningful benefits in daily life.

“Advancing to the finals of this highly competitive global initiative reflects the exceptional scientific foundation we have built at Mount Sinai and the strength of our collaborative research enterprise,” said Eric J. Nestler, MD, PhD, Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and Executive Vice President of the Mount Sinai Health System. He said the collaboration across immunology, neuroscience, metabolism, imaging, and clinical research could help redefine how healthy aging is understood and promoted.

Merad said the team’s selection as a finalist recognizes both the promise of its scientific strategy and the work of its multidisciplinary researchers. The $1 million award will support the continued development of NYC-Vita and help accelerate investigations into interventions that may preserve physical strength, independence, and quality of life. The program is part of Mount Sinai’s broader Healthspan Program, which links biomedical research with clinical care and aims to translate discoveries about aging into practical approaches for preventing or delaying age-related disease.

XPRIZE announced 20 finalist teams at an awards ceremony in Salt Lake City. Ten of those teams, including Mount Sinai, were selected as Milestone 2 Awardees and will share $10 million in direct milestone funding, with each receiving $1 million. Awardees will also gain access to clinical testing resources intended to speed the evaluation of their therapeutic approaches. The finalists represent the United States, South Korea, Japan, and China, underscoring the international competition surrounding efforts to alter the biology of aging. The contest is scheduled to culminate in 2030, when XPRIZE plans to award a grand prize of up to $81 million. Mount Sinai leaders said the team will continue the NYC-Vita trial while seeking additional collaborators and philanthropic support to expand the research and determine whether improvements in immune health can translate into longer, healthier lives.

Subject of Research: Healthy aging, immune-system function, immunosenescence, inflammaging, and interventions designed to extend healthspan.

Article Title: Mount Sinai Team Advances to XPRIZE Healthspan Finals With Immune-Aging Clinical Trial

News Publication Date: August 11, 2026

Web References:
https://www.mountsinai.org/about/healthspan/research
https://profiles.mountsinai.org/miriam-merad
https://profiles.mountsinai.org/zahi-a-fayad
https://profiles.mountsinai.org/fanny-m-elahi
https://profiles.mountsinai.org/thomas-u-marron
https://profiles.icahn.mssm.edu/ryan-w-walker
https://www.mountsinai.org/about/executive-leadership/nestler
https://www.mountsinai.org/about/executive-leadership/brendan-carr

References: XPRIZE Healthspan competition announcement; Icahn School of Medicine at Mount Sinai NYC-Vita clinical trial and Healthspan Program information.

Keywords: healthy aging, healthspan, XPRIZE Healthspan, NYC-Vita, immune aging, immunosenescence, inflammaging, macrophages, clinical trial, Mount Sinai, longevity research, age-related disease, medical imaging, wearable technology, neuroscience, metabolism

The study, titled “Type 2 Diabetes and Longitudinal Changes in Cortical and Trabecular Bone Density, Microarchitecture, and Strength: The Framingham Study,” examined how the skeleton changes over time in older adults with and without type 2 diabetes. The research team used advanced bone imaging to measure not only bone density, but also the architecture and mechanical properties of two distinct parts of bone: cortical bone, the hard outer shell, and trabecular bone, the porous, lattice-like tissue inside.

“Bone density alone does not tell the whole story,” said senior author Elizabeth J. Samelson, PhD, principal investigator of the National Institutes of Health-funded project. People with type 2 diabetes often have bones that appear denser when measured using conventional techniques, yet they experience more fractures than people without diabetes. This apparent contradiction, sometimes called the diabetes bone paradox, has led scientists to investigate whether changes in the quality and organization of bone may be more important than bone mass alone.

The researchers initially expected adults with type 2 diabetes to show greater losses in bone density, microarchitecture, and strength during follow-up. Instead, the longitudinal analysis found that changes in bone were broadly similar between older adults with and without the disease. The result suggests that the elevated fracture risk associated with type 2 diabetes may emerge through pathways that are not captured by conventional measures of bone loss or by changes in the structural properties assessed in this study.

The imaging approach allowed the scientists to analyze cortical and trabecular bone separately. Cortical bone provides much of the skeleton’s resistance to bending and impact, while trabecular bone helps distribute forces through the spine, hips, and other load-bearing regions. Microarchitecture refers to features such as the thickness, spacing, and connectivity of these structures. Even subtle changes can affect how efficiently bone absorbs energy, but the study did not find a diabetes-related pattern of accelerated deterioration in these measures over time.

The study’s findings do not mean that bone health is irrelevant for people with type 2 diabetes. Rather, they indicate that fracture susceptibility may depend on a broader combination of skeletal and non-skeletal factors. Diabetes can affect vision, balance, muscle function, nerve sensation, and reaction time, all of which may increase the likelihood of falling. In addition, complications such as peripheral neuropathy can reduce awareness of foot position and uneven surfaces, potentially making falls more frequent or more severe.

The mechanical behavior of bone may also be influenced by properties that are difficult to measure with standard imaging. Long-term exposure to elevated blood glucose can promote the formation of advanced glycation end products, chemical compounds that accumulate in tissues and may alter the flexibility of collagen. Bone is a composite material made from mineral crystals embedded in a collagen-rich matrix, and changes to that matrix could affect how bone resists cracks even when bone density remains normal or high. The present study underscores the need to investigate these material-level properties more closely.

Alyssa B. Dufour, PhD, lead author and associate scientist at the Hinda and Arthur Marcus Institute for Aging Research at Hebrew SeniorLife, said the team expected to observe greater changes in bone microstructure and strength among participants with type 2 diabetes. Instead, the similar rates of bone loss in the two groups suggest that clinicians and researchers should avoid treating bone density as a complete measure of fracture risk in diabetes. A person may have relatively dense bones while remaining vulnerable because of impaired balance, falls, altered bone material quality, or other disease-related factors.

The work was conducted by investigators from Hebrew SeniorLife, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston University, the University of Calgary, and Cardiovascular Engineering, Inc., using data from the Framingham Heart Study. Funding came from the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Heart, Lung, and Blood Institute. By showing that similar longitudinal bone changes can coexist with different fracture risks, the study adds an important piece to the growing scientific picture of diabetes-related skeletal fragility and may encourage more comprehensive approaches to fracture prevention in older adults.

Subject of Research: People

Article Title: Type 2 Diabetes and Longitudinal Changes in Cortical and Trabecular Bone Density, Microarchitecture, and Strength: The Framingham Study

News Publication Date: 5-Aug-2026

Web References: Diabetes Care article: https://diabetesjournals.org/care/article-abstract/doi/10.2337/dc26-0846/172304/Type-2-Diabetes-and-Longitudinal-Changes-in?redirectedFrom=fulltext

References: DOI: 10.2337/dc26-0846

Keywords: Gerontology, type 2 diabetes, bone health, fracture risk, bone density, cortical bone, trabecular bone, microarchitecture, Framingham Study

The review, led by Dr. Miguel Germán Borda, examined experimental, observational, and interventional research on the relationship between muscle status, physical activity, and Parkinson’s disease. The findings became available online on February 25, 2026, and were published in the journal Neuroprotection on June 1, 2026. The article argues that sarcopenia—the age-related loss of muscle mass, strength, and physical function—may intensify the vulnerability already experienced by people with Parkinson’s disease. In this population, reduced muscle capacity has been associated with poorer mobility, more frequent falls, cognitive difficulties, disability, and a lower quality of life.

“Muscle is a biologically active tissue that has the potential to influence neural function,” said Dr. Salomón Páez-García, the review’s first author. Rather than functioning solely as mechanical tissue that moves the skeleton, muscle can release biochemical signals into the circulation. These signals may affect distant organs, including the brain. This concept has helped shift scientific attention toward the muscle–brain axis, a two-way communication network in which the nervous system controls movement while contracting muscles send molecular messages back to the nervous system.

Across the studies included in the review, several forms of exercise were associated with meaningful benefits for people with Parkinson’s disease. Aerobic activities such as walking and jogging can challenge the cardiovascular system and improve endurance. Resistance training, including weight lifting and squats, targets muscle strength and power. Balance exercises, such as Tai Chi or controlled single-leg standing, address postural stability. Multimodal programs combine these approaches and may be particularly useful because Parkinson’s disease affects multiple dimensions of physical function at the same time.

Regular exercise was linked to improvements in walking ability, balance, mood, muscle strength, cognitive performance, and overall quality of life. Participants in exercise programs also experienced fewer falls and less disability in many of the studies reviewed. Strength and balance training appeared especially important because loss of force and impaired postural control can interact, making everyday movements more difficult and increasing the risk of injury. The researchers emphasize that exercise programs should be adapted continuously to an individual’s physical capacity, symptoms, disease stage, and safety needs.

The biological explanation may involve exerkines, hormone-like molecules released by skeletal muscles during physical activity. Among the most discussed are brain-derived neurotrophic factor, or BDNF; insulin-like growth factor 1, known as IGF-1; irisin; cathepsin B; myostatin; and growth differentiation factor 15, or GDF15. These molecules can travel through the bloodstream and influence tissues throughout the body. Their effects may include regulating inflammation, oxidative stress, energy metabolism, tissue repair, and communication between cells.

In the brain, these signals could be especially important for neurons that produce dopamine in the substantia nigra, a region heavily affected by Parkinson’s disease. Dopamine-producing neurons are vulnerable to mitochondrial dysfunction, chronic inflammation, oxidative damage, and cellular stress. The review describes evidence suggesting that exercise-related signaling may help counter some of these processes by supporting mitochondrial performance, reducing inflammatory activity, and strengthening antioxidant defenses. Exerkines may also promote neuroplasticity, the brain’s ability to adapt, reorganize, and form or reinforce connections between nerve cells.

The proposed mechanism does not mean that exercise can cure Parkinson’s disease or replace established medical treatment. Much of the evidence remains heterogeneous, and the review itself is narrative rather than a single clinical trial designed to prove cause and effect. Exercise studies often differ in duration, intensity, supervision, participant characteristics, and outcome measurements. In addition, the biological actions of individual exerkines are complex and may vary according to age, fitness level, disease severity, medication use, and the type of exercise performed. These factors make it difficult to identify one universal exercise prescription or a single molecule responsible for the benefits.

Even with these limitations, current clinical guidance strongly supports physical activity as a central component of Parkinson’s care. Experts generally encourage people to begin exercising as early as possible and maintain activity for as long as they can, using a combination of aerobic, strength, and balance exercises. The new review adds a molecular perspective to that recommendation: exercise may benefit not only the muscles and cardiovascular system but also the biological environment in which vulnerable brain cells function. Future studies will need to determine which combinations of exercise, intensity, timing, and exerkine activity provide the strongest long-term neuroprotective effects.

Subject of Research: Parkinson’s disease, exercise, sarcopenia, exerkines, and muscle–brain crosstalk

Article Title: Exercise, exerkines, and muscle–brain crosstalk in Parkinson’s disease

News Publication Date: June 1, 2026

Web References: https://doi.org/10.1002/nep3.70032

References: DOI: 10.1002/nep3.70032

Keywords: Parkinson’s disease, physical exercise, sarcopenia, muscle–brain axis, exerkines, neuroprotection, dopamine neurons, neuroplasticity, aging, neuroscience