Sandra Aleksic

There is a growing demand from society for gerotherapeutic interventions that can extend healthspan. Yet the increasing commercialization of insufficiently validated gerotherapeutics threatens to undermine the public confidence and the responsible translation of healthy longevity research into practice. The Unlock Healthy Longevity Conference 2026 convened international experts in Singapore to exchange scientific advances in precision geromedicine, with a particular focus on nutraceuticals and repurposed drugs. Precision geromedicine is increasingly being translated into clinical settings; however, standardized frameworks for clinical evaluation, implementation, quality assurance, and oversight remain insufficiently established. This emerging paradigm emphasises the need for collaboration across multiple stakeholders to support the development of a robust, safe, scalable, and equitable ecosystem. A central theme across the sessions was the need to advance clinical human validation, translation, and the development of standards and clinical guidelines. Panel discussions converged on the importance of developing robust clinical and data infrastructures to generate reproducible evidence capable of informing real-world clinical practice and enable equitable access to healthy longevity. Presentations addressed emerging clinical biomarkers of ageing and data-driven approaches to guide gerotherapeutics, including changes in DNA methylation and skin and gut as organ-level readouts of biological ageing. Several potential candidate gerotherapeutics were discussed, including the nutraceutical compounds urolithin A and ergothioneine, and repurposed drugs such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Additional sessions explored the clinical implementation of gerotherapeutics taking into account ethical, safety, and regulatory considerations. This report summarises the key messages and research priorities presented at the conference.

Obesity, prevalent in almost 40% of Americans aged 60 years and older, ¹ increases the risk for disability, ² justifying weight loss as a strategy for preserving functional independence in older adults. However, declines in muscle mass and bone mineral density (BMD) accompanying rapid and large weight loss might attenuate the benefits of reduced adiposity. ³ In an era of increasingly potent weight-loss pharmacotherapies, long-term follow-up studies are critically needed to guide strategies for healthy aging in older adults with obesity. By examining long-term outcomes in the Look AHEAD study, Semelka et al. ⁴ provide timely insights into how obesity and weight loss in midlife relate to disability in later life. The Look AHEAD study enrolled ∼5100 mid-life and older adults with type 2 diabetes (T2D) and overweight or obesity, who were randomized to intensive lifestyle intervention (ILI, 7% or greater weight loss) or diabetes support and education (control). ⁵ During the 10-year intervention, ILI was associated with a slower decline in physical function, with stronger effects in older compared to younger participants, ⁵ which was projected to reduce late-life disability. ⁶ However, during the 6 years of post-intervention follow-up, no differences were observed in physical function between ILI and control. ⁷ Semelka et al. ⁴ report on the impacts of ILI and obesity on late-life disability during the 10 years of post-intervention follow-up (ie, up to 20 years after randomization) in 1,200 surviving Look AHEAD participants. The study reports age-dependent effects of midlife ILI on late-life disability: Among participants younger than 70 at the first post-intervention visit (ie, 60 years at randomization) experienced 50% higher odds for severe mobility disability after ILI. ⁴ Class 2 obesity (ie, body mass index [BMI] ≥35 kg/m²) at the first-post intervention visit was associated with higher odds for late-life mobility disability, severe disability, and IADL disability, but these findings did not extend to class 1 obesity (BMI 30-35 kg/m²). ⁴

Background: Older adults with exceptional longevity—and their offspring—are protected from age-related diseases and have a prolonged health span. Prior research suggests that offspring of parents with exceptional longevity have larger temporal and sensorimotor cortices in mid to late-adulthood—but the association between brain health and parental longevity is not well understood in older adults. This study aimed to identify a gray matter volume pattern (or network) associated with parental longevity in older adults—and to determine if individual expressions of this gray matter pattern vary with cognitive performance. Methods: Participants consisted of 139 older adults of Ashkenazi Jewish descent from the LonGenity study (M age 79.4 ± 6.5 years; 56.11% women). Eighty-four (60.4%) were offspring of parents with exceptional longevity and 55 (39.6%) were offspring of parents with usual survival. A gray matter network associated with parental longevity was derived with multivariate covariance-based analyses that were adjusted for potential confounders. Participant-specific expressions of this network were then regressed against cognitive test performances. Results: The derived gray matter covariance network associated with parental longevity was primarily composed of frontal, insular, and hippocampal regions. The extent to which older adults displayed this pattern was associated with overall cognition, Free Recall, Digit Symbol Substitution, Boston Naming, and Trail Making Test A performance. Conclusions: Parental longevity is associated with a widespread network of brain regions in aging. This brain network also varies as a function of cognitive performance.

Context: Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counterregulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally yet is not feasible therapeutically. Objective: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally induced HAAF. Design: Randomized, double-blinded, placebo-controlled crossover study. Setting: Academic research center. Participants: Healthy nondiabetic volunteers. Interventions: Paired 2-day studies, 5 to 10 weeks apart, each consisting of 3 consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): 2 on day 1 with administration of intranasal naloxone vs placebo, followed by the third episode on day 2. Main Outcome Measures: Differences in counterregulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs placebo studies. Results: Out of 17 participants, 9 developed HAAF, confirming variable interindividual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and GH responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. Conclusion: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable interindividual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic–pituitary‐testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90–106 years. We found that 94% of men exhibited preserved hypothalamic–pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging‐related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic–pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience‐guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA‐approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)‐like study involving such candidate gerotherapeutics.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this “glucose effectiveness” is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). K_ATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central K_ATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of K_ATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the K_ATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central K_ATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.