Biology of Ageing

Insights from Dr. Nir Barzilai’s Gerotherapeutics Research

 

Ageing is not just a passage of time—it’s a biological process that drives the onset of many chronic diseases, from diabetes to Alzheimer’s. Dr. Nir Barzilai, a leader in aging research, argues that by targeting the biology of aging, we can extend both healthspan and lifespan, fundamentally changing how we approach age-related diseases and quality of life.

The Biology of Ageing: Hallmarks and Targets

Ageing is driven by a set of biological hallmarks, including metabolic dysregulation, mitochondrial dysfunction, inflammation, immune decline, and cellular senescence, among others. Each hallmark offers a potential target for drug development. Interventions that modulate these hallmarks have already shown promise in extending healthy lifespan in animal models and, in some cases, in humans.

Key Hallmarks of Ageing:

  • Metabolic Dysregulation

  • Epigenetic Changes

  • Mitochondrial Dysfunction

  • Inflammation and Immune Decline

  • Loss of Proteostasis

  • Cellular Senescence

  • Stem Cell Dysfunction

  • Chromosome Maintenance Issues

Repurposed Drugs: The Rise of Gerotherapeutics

Several FDA-approved drugs are being repurposed as gerotherapeutics—medications aimed at delaying aging and its related diseases. Notable examples include:

  • Metformin: Traditionally used for type 2 diabetes, metformin has demonstrated effects on multiple hallmarks of aging, including improved mitochondrial function, reduced inflammation, and enhanced DNA repair. Studies show that metformin users have lower risks of cardiovascular disease, cancer, cognitive decline, and mortality, even among non-diabetics.

  • SGLT-2 Inhibitors: These drugs, used for diabetes and kidney disease, have shown benefits in extending lifespan and reducing cardiovascular and all-cause mortality in clinical trials1.

  • Rapamycin and Rapalogs: Known for their impact on mTOR signaling, these drugs extend lifespan in animal models and are being explored for human use1.

  • Bisphosphonates and GLP-1 Agonists: Originally for bone health and diabetes, respectively, these drugs are now linked to improved healthspan and reduced mortality in broader populations.

Comparative Gerotherapeutic Scores

Clinical Evidence: Metformin as a Case Study

Metformin stands out for its broad effects across the hallmarks of aging. Clinical studies have shown that:

  • It delays the onset of type 2 diabetes and cardiovascular disease.

  • It is associated with reduced cancer incidence and lower risk of cognitive decline.

  • In COVID-19, metformin reduced the risk of severe outcomes and long COVID when started early.

  • In randomized trials, metformin users under 80 had a significantly lower risk of dementia compared to those on alternative therapies.

The Genetics of Longevity

Genetic studies of centenarians reveal that longevity is not about having a “perfect genome” but about resilience—protective genotypes that interact with the environment to delay or escape age-related diseases. Large-scale exome sequencing projects are identifying rare protective variants and pathways, such as insulin/IGF-1 and mTOR signaling, that are enriched in long-lived individuals.

Challenges and Opportunities

While the promise of gerotherapeutics is immense, several challenges remain:

  • Defining Gerotherapeutics: There is ongoing debate about the criteria for classifying a drug as a gerotherapeutic.

  • Clinical Trial Design: Trials must be designed to measure effects on aging biology, not just single diseases.

  • Regulatory Pathways: Should FDA-approved drugs be repurposed now, or do we need more evidence?

The Way Forward

Targeting the biology of ageing represents a paradigm shift in medicine. Repurposed drugs like metformin and SGLT-2 inhibitors are leading the way, showing that it is possible to extend healthy years of life. As research advances, the integration of genetics, clinical trials, and big data will accelerate the discovery of new gerotherapeutics, offering hope for longer, healthier lives.