A Conservative View of the Geroscience Endeavor
An archly conservative viewpoint links establishment academia ("this thing you are doing has not yet been proven beyond all doubt to work") to the thought leadership of Big Pharma ("this thing you are doing has not yet been proven beyond all doubt to generate profit"). Both sides look at the billions in funding devoted to the growing longevity industry, and the decades of painstaking scientific work that set the foundation for that industry, and see an ongoing test in progress, as yet unfinished and the result undetermined. Can aging in fact be slowed or reversed in a practical way in humans as it can in laboratory species?
There are those who determinedly take a wait and see approach, wanting the concrete answer. Obviously a great many other people, scientists, entrepreneurs, patients, and patient advocates, are less conservative than this, otherwise there would be no longevity industry. Many lines of work that lead to potential rejuvenation therapies are highly promising, and the only remaining question is how much additional life they can provide to members of our own species. The future is ever uncertain, but one doesn't win victories by refraining from participation.
Today's open access review, being a very broad survey of everything that might fall into the purview of the diverse longevity industry, lumps together a range of very different approaches under one heading. I think this a mistake, a category error that is becoming common. At the very least one should not be placing NAD+ upregulation (unreliable animal data, small effect size, long history of failed human trials for a range of conditions) into equivalence to senolytics to clear senescent cells (reliable and extensive animal data, large effect size for reversal of age-related conditions, mixed data from only a few early human trials). These are very different classes of therapy with very different supporting evidence, and emerge from very different philosophies of development.
Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. This review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes.
Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD+ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies.
Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety.