The Longevity Genes: New Frontiers in Ageing Biology

The Longevity Genes: New Frontiers in Ageing Biology

The study of human ageing has pivoted from descriptive gerontology to precision geroscience, driven largely by the identification of specific genes that exert substantial influence over lifespan and healthspan.

These ‘longevity genes’ often regulate fundamental cellular processes, offering crucial insight into the mechanisms of resilience against age-related decline.

Understanding their function and modulation is now central to developing effective interventions against chronic diseases and extending the period of human vitality.

Key Regulators of Cellular Homeostasis

A small cohort of genes has emerged as particularly significant in modulating longevity across diverse populations.

Klotho (KL)

The Klotho gene encodes a protein that acts as an endocrine factor, a transmembrane protein, and a circulating hormone. Its primary biological role involves binding to various receptors, most famously regulating phosphate and calcium homeostasis via interaction with Fibroblast Growth Factor 23 (FGF23).

Relevance to Ageing: Klotho is widely referred to as an anti-ageing protein; its deficiency in animal models results in premature ageing phenotypes, including atherosclerosis, osteoporosis, and cognitive impairment.

Conversely, overexpression of the secreted form of Klotho (s-KL) has been shown to extend lifespan and improve physical, cognitive, and bone health in adult mice, demonstrating a pleiotropic protective effect across multiple organ systems¹ .

Therapeutic Implications: The success of Klotho gene therapy in animal models suggests sKL delivery via vectors, such as adeno-associated viruses (AAV), is a viable therapeutic avenue.

Furthermore, lifestyle interventions, such as exercise and dietary components like vitamin C and fiber, are associated with higher Klotho levels, offering non-pharmacological methods of maintenance² .

Apolipoprotein E (APOE)

APOE is crucial for lipid transport, particularly in the brain and periphery. It possesses three common alleles: ϵ2, ϵ3, and ϵ4.

Relevance to Ageing: While the ϵ3 allele is considered neutral, the ϵ4 allele is the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), and its presence is associated with decreased odds of extreme longevity.

In contrast, the ϵ2 allele is strongly associated with exceptional longevity and provides protection against AD and cardiovascular disease (CVD)³ . This antagonistic pleiotropy highlights APOE’s dual role in both lifespan and disease risk.

Therapeutic Implications: Therapeutic focus is shifting toward targeting the pathogenic effects of APOE4, potentially through small molecules that alter its conformation or prevent its neurotoxic interactions with amyloid-beta and tau proteins.

Understanding how the protective ϵ2 allele mediates lipid metabolism is also key to developing CVD preventative strategies⁴ .

Genome and Metabolic Stabilisers: The Sirtuin Family

Sirtuins are a family of NAD⁺ -dependent deacetylase enzymes that link cellular energy status to gene regulation, DNA repair, and stress resistance.

Sirtuin 1 (SIRT1)

SIRT1 acts as a master metabolic sensor. Its biological function involves deacetylating numerous transcription factors, including p53 and FOXO, to promote stress resistance, DNA repair, and mitochondrial biogenesis.

Relevance to Ageing: High SIRT1 activity mimics the anti-ageing effects of caloric restriction, offering widespread protection against metabolic dysfunction, inflammation, and neurodegeneration⁵ .

Therapeutic Implications: Small-molecule SIRT1-Activating Compounds (STACs) have been developed to enhance its activity. While the efficacy of initial compounds (like Resveratrol) has been debated, newer, more potent analogues are being explored in clinical trials to improve metabolic health and systemic resilience in older adults⁵ .

Sirtuin 6 (SIRT6)

SIRT6 is predominantly chromatin-associated, functioning as a vital caretaker of the genome. Its primary role is to maintain genomic stability by regulating DNA repair, telomere integrity, and heterochromatin structure, especially silencing repetitive genetic elements (retrotransposons)⁶ .

Relevance to Ageing: Deficient SIRT6 leads to genomic instability and a progeroid phenotype. Intriguingly, rare variants of SIRT6 found in human centenarians have been shown to possess enhanced DNA repair capabilities and more robust silencing activity, correlating with a survival advantage⁶ ' ⁷ .

Therapeutic Implications: Strategies to enhance SIRT6 expression or activity are compelling targets for rejuvenation. This includes developing activators that specifically boost its ribosylase activity, which is central to its genome-protective functions⁷ .

Transcription and Mitochondrial Integrity

Forkhead Box O3 (FOXO3)

FOXO3 is a highly conserved transcription factor regulated by the PI3K/Akt signalling pathway. When inactive, it is sequestered in the cytoplasm; under conditions of cellular stress (e.g., oxidative stress, growth factor deprivation), it translocates to the nucleus to induce the transcription of genes involved in DNA repair, stress resistance, and apoptosis⁸ .

Relevance to Ageing: FOXO3 is one of the most consistently replicated longevity-associated genes in human populations worldwide. Longevity-associated single nucleotide polymorphisms (SNPs) in FOXO3 correlate with a significantly lower incidence of cardiovascular disease and a robust cellular response to chronic stress, particularly in elderly men with existing cardiometabolic conditions⁸ ' ⁹ .

Therapeutic Implications: Pharmacological manipulation to stabilise FOXO3 activity or promote its nuclear translocation represents a strategy to enhance cellular resilience and maintain vascular homeostasis, thereby delaying age-related vascular diseases⁸ .

CISD2 (CDGSH Iron Sulfur Domain 2)

CISD2 encodes a transmembrane protein located primarily at the mitochondrial outer membrane and the endoplasmic reticulum, notably at the mitochondria-associated membranes (MAMs). Its biological role is critical for regulating mitochondrial function and cytosolic Ca²⁺ homeostasis.

Relevance to Ageing: CISD2 is essential for mammalian lifespan control. Its expression declines with age, and its deficiency leads to mitochondrial dysfunction, increased reactive oxygen species (ROS) production, and a shortened lifespan in mice¹⁰. Conversely, persistent, high-level expression of CISD2 can delay age-associated degeneration in skeletal muscles, skin, and the heart, effectively rejuvenating aged organ function¹⁰ ' ¹¹ .

Therapeutic Implications: CISD2 offers a novel target for cardiac ageing, as its upregulation has been shown to reverse structural and functional abnormalities in the aged heart¹⁰ . Furthermore, certain natural compounds, such as Hesperetin, have been shown to activate CISD2 expression, providing a potential pathway for pharmacological intervention against agerelated degeneration¹¹ .

A Forward-Looking Perspective

The study of longevity genes has moved from simple association studies to deep mechanistic understanding, revealing a network of resilience pathways rather than a single master switch.

The future of geroscience lies in polypharmacy, developing interventions that simultaneously target multiple longevity pathways (e.g., enhancing Klotho’s systemic protection while boosting SIRT6’s genomic fidelity and stabilising FOXO3’s stress response).

The encouraging success of gene therapy models in animals, particularly with Klotho and CISD2, suggests that the concept of therapeutic gene modulation to maintain youthful cellular function is transitioning rapidly from theory to translational reality.

This convergence of genomics, biochemistry, and advanced delivery systems promises to revolutionise our approach to health, making resilience, not just disease treatment, the primary objective of medical care.

References

1. Roig-Soriano, L., et al. Klotho gene therapy prolongs the lifespan of adult mice and ameliorates physical and cognitive ageing. Molecular Therapy 33, 5 (2025).

2. Dubnov, S., et al. Knockout of the longevity gene Klotho perturbs aging and Alzheimer's disease- linked brain microRNAs and tRNA fragments. Communications Biology 7, 1 (2024).

3. Raghavachari, N. The Impact of Apolipoprotein E Genetic Variability in Health and Life Span. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 75, 12 (2020).

4. Bae, H., et al. Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants. International Journal of Molecular Sciences 23, 19 (2022).

5. Hallows, K. R. & Yu, Z. Sirtuins at the Service of Healthy Longevity. International Journal of Molecular Sciences 22, 23 (2021).

6. Vera, E. & Blasco, M. A. A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A. The EMBO Journal 40, 19 (2021).

7. Simon, M., et al. Sirtuin 6: linking longevity with genome and epigenome stability. Cellular and Molecular Life Sciences 79, 3 (2022).

8. Li, Y., et al. Longevity Factor FOXO3: A Key Regulator in Aging-Related Vascular Diseases. Frontiers in Cardiovascular Medicine 8, 778674 (2021).

9. Lee, K. M., et al. Longevity gene could be key in reducing risk of death for men with chronic disease. Journal of Gerontology 76, 3 (2021).

10. Chi, H. F., et al. Rejuvenating the Aging Heart by Enhancing the Expression of the Cisd2 Prolongevity Gene. Molecular Therapy: Methods & Clinical Development 23, 155–168 (2021).

11. Hsu, Y. M., et al. Rejuvenation: Turning Back Time by Enhancing CISD2. International Journal of Molecular Sciences 2022, 23(22),