Aging is the strongest risk factor for most chronic diseases; however, medicine has historically treated each condition individually. Geroscience is a new discipline that aims to define and modify aging-related biological pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival.
A review in JAMA outlines the aims, methods, recent advances, and ongoing challenges of geroscience.
The review was authored by Stephen B. Kritchevsky, PhD, Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, North Carolina, and Steven R. Cummings, MD, California Pacific Medical Center Research Institute, San Francisco, and Department of Epidemiology and Biostatistics, University of California, San Francisco.
In Italy, the prevention of aging is particularly relevant. Data from the Italian National Institute of Statistics (2023) show that 24.1% of the Italian population — 14.2 million people — is older than 65 years, making Italy the world’s second-oldest country after Japan.
By 2050, 35% of Italians are expected to be 65 years or older.
The 2023 Osservasalute Report found that 87% of Italian senior citizens live with at least one chronic condition, and 67% have two or more, at an annual cost to the National Health Service exceeding €66 billion.
Traditional Limits
Disease-specific prevention has shown notable results. For example, statins lower the risk for composite cardiovascular events by 28% in primary prevention.
But the authors emphasized significant limitations: “Disease-focused approaches to prevent and treat conditions do not address age-related health issues such as fatigue, mobility limitations, and frailty that are common even in the absence of overt disease.”
Frailty illustrates this gap. In the Cardiovascular Health Study, which followed more than 5200 adults for over 30 years, 16% were frailer than expected based on their comorbidities. “After adjusting for comorbidity count, the frailest group experienced 2-3 fewer years of disability-free life compared with those who were not frail,” the authors wrote.
Age is a disproportionate risk factor. During the COVID-19 pandemic, the mortality rate was seven times higher in those aged 85 years or older (1.6%) than in those aged 65-74 years (0.2%).
Multimorbidity also rises sharply with age, and “the incidence of developing a third disease among those with two chronic medical conditions is 5.2% among those aged 50-59 years and 16% in those aged 70-79 years,” the authors wrote.
The authors emphasized that single-disease paradigms fail to account for age as the strongest determinant of risk for many diseases, including coronary heart disease, cancer, chronic obstructive pulmonary disease, stroke, dementia, and chronic kidney disease.
Biologic Age
The geroscience hypothesis holds that biologic aging is a process distinct from chronologic aging.
Biologic age quantifies how much a person’s physiology deviates from what would be expected of their chronologic age. For example, “a 50-year-old woman with a maximal oxygen consumption of 32 mL/kg/min, typical of women 10 years younger, would have a biologic age of 40 years,” the authors noted.
Age advancement, defined as the difference between biologic and chronologic age, predicts mortality and other age-related outcomes independently of chronologic age. For example, “an individual with a biologic age 8.3 years older than their chronologic age, based on DNA methylation, had a 2.2-fold higher hazard of death than a person with a similar chronologic age.”
Survivors of childhood cancer also show accelerated biologic aging: “At an average age of 35 years, survivors were biologically 2.2-6.5 years older than age- and sex-matched controls using seven different approaches based on physiologic measures or DNA methylation.”
Cellular Pathways
Biologists specializing in aging have identified cellular pathways that influence lifespan, defined as the total length of life, and health span, defined as the length of life spent free from disease. These pathways involve multiple aspects of cellular physiology, including the accumulation of somatic DNA variations and the regulation and accuracy of DNA transcription.
Regulation includes the maintenance of telomeres and regions of repetitive DNA sequences at the ends of chromosomes that shorten with replication. When telomeres are too short, DNA replication cannot occur. Methylation of DNA bases and other epigenetic changes can alter gene transcription with age.
Maintaining protein structure and function, or protein homeostasis, is strongly associated with aging. In particular, autophagy removes damaged intracellular proteins. Other pathways are related to nutrient sensing, such as signaling induced by amino acids, insulin, or insulin-like growth factor 1, sustaining stem cell populations, and preserving mitochondrial function.
Variations in mitochondrial DNA accumulate with age. One genetic variant, m.3243A>G, is linked to inherited mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome.
In a cohort of 789 adults aged 70-80 years, approximately 33% carried this variant in 6%-19% of their leukocyte mitochondrial DNA. These individuals showed slower performance, greater arterial stiffness, and reduced grip strength.
Participants with a higher abundance of this variant had increased 17-year mortality rates from dementia and stroke compared with those with the lowest abundance.
Caloric Restriction
Caloric restriction is the most extensively studied intervention in geroscience.
The authors reported important results: “In one strain of mice, a 20% caloric restriction increased median survival from 785 to 1096 days in females (40%) and from 807 to 999 days (24%) in males.”
The CALERIE trial provided the first evidence of this in humans. The CALERIE trial randomized 218 adults without obesity, aged 21-51 years, to a 2-year intervention comparing caloric restriction with no caloric restriction. The results showed significant cellular changes: Caloric restriction upregulated autophagy and DNA repair and downregulated the inflammatory response, as measured by rank-based pathway enrichment analysis. Participants in the restriction group aged 0.6 years less over the 24 months of the study than participants with no caloric restriction.
Incretin therapies such as semaglutide and tirzepatide offer durable caloric restriction surpassing behavioral interventions and significantly reducing clinical risks in adults with or without type 2 diabetes. Semaglutide (2.4 mg/wk) achieved 14.9% weight loss over 68 weeks. These therapies also lower cardiovascular events by 20% and all-cause mortality by 19%.
Metformin
The review also focuses on metformin, a biguanide and first-line treatment for type 2 diabetes, which may slow age-related biologic processes through its effects on multiple aging pathways.
“Metformin inhibits mitochondrial complex I, which increases AMPK [adenosine monophosphate-activated protein kinase] activity, thereby inhibiting mTOR complex 1 and activating peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These actions enhance autophagy and mitochondrial biogenesis.”
Observational data suggest broad benefits. Among 5528 Veterans Affairs patients with type 2 diabetes, metformin users had a lower incidence of neurodegenerative diseases, including dementia, Parkinson’s disease, Huntington’s disease, and mild cognitive impairment compared with nonusers (11.48 vs 25.45 per 1000 person-years).
Among patients with type 2 diabetes hospitalized with COVID-19 infection, metformin use was associated with a lower 28-day mortality rate (16.0% vs 23.6%). But the authors noted that “Studies of the effects of metformin on patients with diabetes and prediabetes have had inconsistent results,” highlighting the need for studies designed to measure aging-related outcomes.
Rapamycin
Rapamycin, developed to prevent transplant rejection, has shown antiaging effects by acting on mTOR, a regulatory component of the cellular nutrient-sensing pathway. “Reducing mTOR activity increases cellular autophagy,” the authors noted.
“Inhibition of mTORC1 [mTOR complex 1] by rapamycin increased lifespan in multiple model organisms, including mice, even when treatment began at 20 months of age.”
Human evidence is promising but limited. “In a clinical trial of 218 adults aged 65 years or older, 6 weeks of everolimus at 0.5 mg daily or 5 mg weekly was safe and significantly improved the response to influenza vaccination compared with placebo.”
The authors noted that “Lower intermittent doses may improve aging-related biologic pathways while producing fewer adverse effects.”
Senescent Cells
Senolytic drugs are among the most novel geroscience strategies.
“Senescent cells no longer divide, resist apoptosis, and secrete inflammatory cytokines, chemokines, proteases, and other substances collectively known as the senescence-associated secretory phenotype,” the authors explained.
The accumulation of these cells has been documented. Senescent cells accumulate with age.
In a survey of senescent cell markers with age in human tissues, the concentration of kidney cells expressing the senescence marker p21 was 1% in five older donors aged 71-79 years, compared with less than 0.2% in five younger donors aged 19-30 years.
In preclinical studies, eliminating p16-positive cells with AP20187, which induced apoptosis in genetically modified mice expressing p16, increased the median lifespan by up to 27% (from 624 to 793 days) and reduced cancer mortality, delayed cataract formation, and enhanced spontaneous physical activity.
Early clinical trials have shown that this strategy is safe and that senolytic treatment reduces the number of cells expressing p16 and p21, two senescence markers.
Regulatory Hurdles
According to the authors, a significant obstacle to the development of effective prevention strategies is the current regulations. “The FDA does not recognize slowing aging or reducing aging-related conditions, such as sarcopenia or mobility limitation, as approved indications.”
The authors emphasized that “evaluating approved drugs for age-modifying effects will require broad inclusion criteria, alternative dosing regimens, and longer study durations than those used to establish therapeutic efficacy for their original indications. If multiple clinical trials, including those testing potential indications such as peripheral artery disease, heart failure, or osteoporosis, collect these outcomes, response patterns may be identified to guide future studies with measures more directly linked to specific aging-related biologic targets.” The authors also cautioned about the limitations: “This review had several limitations. First, it was not a systematic review, and the quality of the included evidence was not formally assessed. Second, geroscience is a rapidly evolving field, and relevant references may have been missed.”
Conclusion
Despite these limitations, the authors concluded that “therapies that target aging biology, including caloric restriction, metformin, senolytics, and rapalogs, may slow disease development and progression as well as functional decline in humans.”
This represents a fundamental paradigm shift. Instead of waiting for specific diseases to develop and then treating them individually using disease-specific approaches, geroscience proposes modifying the fundamental biological processes that increase susceptibility to age-related comorbidities.
Therapies that target the biology of aging could not only extend lifespan but, more importantly, improve the “health span” of the years lived in good health without disability or chronic disease. In today’s era of rapid population aging, these strategies could help turn aging from a problem to an opportunity, moving beyond the limits of traditional approaches.
This story was translated from Univadis Italy.
