he aging population is steadily increasing. The World Health Organization (WHO) estimates that 1 in 6 people, or 2.1 billion, are expected to be over age 60 by 2030 (ref. 1 ). Chronological age is the major predictor for most of the diseases that account for the bulk of morbidity, mortality and health costs across low-, middle-and high-income countries [2][3][4][5][6][7] .Aging progresses throughout the lifespan can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children 6,[8][9][10][11][12] . Indeed, fundamental aging processes can operate even before conception, for example, in the context of aged oocytes linked to Down syndrome 12,13 . A fundamental aging mechanism that has gained increasing attention is cellular senescence. Senescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases. After the first reports of senolytic drugs (agents that selectively eliminate senescent cells) in 2015 (ref. 14 ), promising results from preclinical studies have facilitated progression to early-phase clinical trials evaluating the safety and efficacy of senolytics, some of which have now been published (Table 1).Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence 3,15 . The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction (including the geriatric syndromes such as frailty, immobility, sarcopenia/ muscle wasting, mild cognitive impairment and incontinence) and loss of resilience (for example, decreased ability to recover from stresses such as injury, surgery, chemotherapy or infections or to mount an antibody response to immunizations) 3,[15][16][17][18] . The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others 6 . For example, interventions that target cellular senescence tend to attenuate other

Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation.Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curativeintent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method.Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P ¼ 0.0106).Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.