New review explores metformin’s expanding potential in vascular health, geroscience and healthspan extension.
Few familiar medicines continue to generate momentum in geroscience, but metformin remains an exception – not with fanfare, but with the quiet accumulation of mechanistic evidence, translational promise and clinical familiarity. A new review article published in Drugs & Aging makes the case for repurposing metformin not only as a treatment for type 2 diabetes, but as a therapeutic agent in vascular aging – a key contributor to cardiovascular morbidity and, increasingly, a focal point for longevity research.
Authored by Rooban Sivakumar and colleagues at SRM Medical College in India, the paper delves into the layered mechanisms through which metformin may modulate the degenerative processes underpinning vascular aging. These include oxidative stress, endothelial dysfunction and arterial stiffening – hallmarks of vascular decline that, while not diseases in themselves, shift the biological balance toward pathology with age. “Metformin… goes beyond glycemic control, rendering it a geroprotector potentially suitable for broader application in age-related vascular decline,” the authors write [1].
Longevity.Technology: The reframing of metformin as a vascular geroprotector marks a turning point – not just for how we think about this old drug, but for how we think about aging itself. This isn’t merely metabolic modulation; it’s a challenge to the disease-first model of cardiovascular care. By identifying endothelial dysfunction and arterial stiffening as upstream, modifiable aging processes – and not inevitable by-products – the authors make a compelling case for deploying existing drugs preventively and proactively. And with its affordability, accessibility and long safety record, metformin is a candidate that could scale globally, not just in wealthy, well-insured cohorts.
But there’s a bigger question under the surface: what will it take to translate evidence like this into actual practice? We don’t lack mechanistic clarity, nor do we lack real-world data – what we lack is regulatory and institutional agility. Until drugs like metformin can be prescribed for aging biology, we remain focused on symptoms rather than the systems driving them. This paper reads as a call to arms – for better trial design, better endpoints and, ultimately, better frameworks that reflect the 21st-century reality: aging is modifiable, and longevity starts with the vasculature. We spoke to lead author Rooban Sivakumar to find out more.
Mechanisms and markers
The review explores metformin’s activation of AMP-activated protein kinase (AMPK), a cellular energy sensor associated with enhanced longevity and metabolic regulation. In vascular tissues, AMPK activation appears to mitigate oxidative stress and enhance nitric oxide bioavailability – both critical for maintaining endothelial function.
The paper also highlights other relevant pathways: inhibition of NF-κB signalling, suppression of vascular smooth muscle cell senescence, reductions in reactive oxygen species and improved lipid handling via PCSK9 modulation. These mechanisms appear to converge on structural benefits – reduced arterial stiffness, slower plaque formation and improved endothelial integrity – all early markers of vascular aging with known links to mortality [1].
Clinically, metrics such as pulse wave velocity (PWV) and carotid intima–media thickness (cIMT) are presented as promising endpoints, with well-established associations to vascular stiffness, cardiovascular risk, and mortality. As the authors note, “both clinical and preclinical studies revealed empirical data” supporting improvements in these markers with metformin use [1]. However, while PWV and cIMT offer valuable insights into vascular aging, they are not yet universally recognized as validated surrogate endpoints by regulatory agencies. This creates a challenge for formally repurposing metformin in aging-focused trials, underscoring the need for continued research to establish consensus on aging-specific biomarkers that can support clinical approval.
While the biological case grows stronger, clinical translation remains cautious. “We’re getting close, but not quite there yet,” lead author Rooban Sivakumar told Longevity.Technology. “Metformin has shown real promise, even in individuals without diabetes, by targeting key drivers of vascular aging, including inflammation, oxidative stress, and endothelial dysfunction. But we need to stay realistic. The field still lacks validated aging endpoints, and trials are complex.”
He also points to a shifting landscape in vascular health. “We’re now in an era where vascular aging is no longer just a concern of the elderly; early vascular aging is becoming more common due to factors like poor diet, stress, pollution and metabolic syndromes. Even if early studies are promising, we still need extensive, long-term studies like the TAME trial, particularly designed around aging, whose findings might revolutionise our use of metformin in preventative aging.”
A shift in positioning
The paper gently but firmly signals a shift in how we might manage aging-associated vascular decline. No longer viewed simply as a prelude to cardiovascular disease, vascular aging is being reframed as an intervention point in its own right. The search for scalable, cost-effective strategies is ongoing – and here, metformin presents a rare opportunity.
It offers what few longevity candidates can: a long-established safety record, generic status that reduces cost barriers, and plausible efficacy across a spectrum of age-related pathologies. Its effect extends well beyond glucose regulation – touching inflammation, vascular stiffness and endothelial integrity – regardless of diabetic status.
From evidence to application
For clinicians and policymakers, however, prescribing metformin for aging remains out of reach. As the authors suggest, clinical trials with endpoints tailored to vascular aging – rather than broad cardiovascular events – will be key to shifting regulatory frameworks [1]. While large studies such as the TAME trial may lay groundwork, the review makes clear that targeted investigations are warranted.
Whether this evidence translates into policy and practice will depend not only on biomarker shifts or mortality curves, but on how institutions define risk, aging and prevention itself.
Sivakumar agrees, noting that current frameworks are still ill-equipped to accommodate preventative gerotherapeutics. “To move forward, we need to rethink how we define and address aging in medicine,” he says. “Right now, aging isn’t considered a treatable condition, so drugs like metformin can’t be formally tested or approved, even when the science is strong.”
He adds: “One major shift we need is for regulators to accept vascular aging-related biomarkers, like pulse wave velocity or carotid intima–media thickness, as valid trial endpoints. Also, aging doesn’t start at 60 or 70 anymore. With early vascular aging on the rise, we need policies that support the preventive use of drugs along with lifestyle modifications before the damage is done.”
Combination approaches may also play a role in bridging the gap between mechanistic potential and clinical uptake. “Metformin helps maintain cellular health by targeting aging pathways like AMPK, mTOR and SIRT1,” notes Sivakumar. “Though it’s not the whole answer, it’s a fantastic basis from which to stack other treatments for a more focused, effective treatment on vascular aging.”
Metformin’s story, it seems, is not yet complete. As researchers continue to trace the tangled roots of vascular aging, this unassuming molecule may yet take on a new role – not as a wonder drug, but as a quietly effective pillar in the architecture of healthy longevity.
[1] https://link.springer.com/article/10.1007/s40266-025-01215-3
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