Ageing is a complex, multifactorial biological process that leads to a progressive decline in physiological integrity, increased vulnerability to disease, and ultimately death. In recent decades, research has converged on nine key biological mechanisms - collectively known as the Hallmarks of Ageing. These interconnected processes represent the core drivers of cellular and systemic ageing across species.

1. Genomic Instability

One of the foundational mechanisms of ageing is genomic instability, which refers to the accumulation of DNA damage over time. Sources of genomic stress include exogenous factors (e.g., radiation, toxins) and endogenous processes (e.g., replication errors, reactive oxygen species). Persistent DNA damage can result in mutations, chromosomal aberrations, and activation of cell death or senescence pathways. These effects contribute significantly to the ageing phenotype and the onset of age-related diseases, such as cancer and neurodegeneration (López-Gil, Pascual-Ahuir and Proft, 2023).

2. Telomere Attrition

Telomeres are repetitive nucleotide sequences that cap the ends of chromosomes, safeguarding genomic integrity. With each cell division, telomeres shorten, eventually triggering replicative senescence or apoptosis when critically short. Telomere attrition is associated with tissue dysfunction, immunosenescence, and increased susceptibility to chronic disease, making it a prominent marker of biological ageing (Oeseburg et al., 2010).

3. Epigenetic Alterations

Ageing is accompanied by widespread epigenetic reprogramming, including DNA methylation changes, histone modifications, and altered non-coding RNA expression. These alterations disrupt gene regulation and contribute to age-associated phenotypes such as inflammation, impaired repair mechanisms, and cancer predisposition. Epigenetic clocks—based on DNA methylation—are emerging as powerful biomarkers of biological age (Dhar, Moodithaya and Patil, 2022).

4. Loss of Proteostasis

Proteostasis (protein homeostasis) is essential for cellular function and is maintained by molecular chaperones, the ubiquitin-proteasome system, and autophagy. With age, these systems become compromised, leading to the accumulation of misfolded or aggregated proteins. Loss of proteostasis is a key feature in neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s disease (Taylor and Dillin, 2011).

5. Deregulated Nutrient Sensing

Ageing is closely linked to changes in nutrient-sensing pathways, including insulin/IGF-1 signaling, mTOR, AMPK, and sirtuins. These pathways regulate metabolism, stress responses, and autophagy. Caloric restriction and pharmacological interventions targeting nutrient sensing have demonstrated lifespan extension in multiple model organisms, underscoring their central role in ageing (Efeyan, Comb and Sabatini, 2015).

6. Mitochondrial Dysfunction

Mitochondria are critical for energy production, redox balance, and apoptosis regulation. Ageing is associated with mitochondrial DNA mutations, decreased oxidative phosphorylation, and increased generation of reactive oxygen species. Mitochondrial dysfunction leads to reduced cellular energy and contributes to systemic metabolic decline and inflammation (Somasundaram et al., 2024).

7. Cellular Senescence

Cellular senescence refers to a state of permanent cell cycle arrest in response to stress or damage. Senescent cells secrete pro-inflammatory cytokines, growth factors, and proteases—a profile termed the senescence-associated secretory phenotype (SASP). While senescence serves a protective function early in life, its accumulation in tissues drives chronic inflammation and tissue dysfunction in ageing (Mylonas and O’Loghlen, 2022; Zhang et al., 2022).

8. Stem Cell Exhaustion

Stem cells are essential for tissue regeneration and repair. With age, their numbers and regenerative capacity decline—a phenomenon termed stem cell exhaustion. This contributes to impaired tissue homeostasis, delayed wound healing, and organ degeneration. Rejuvenation strategies targeting stem cell niches hold potential for combating age-related degeneration (Rezazadeh and Ellison-Hughes, 2024; Oh, Lee and Wagers, 2014).

9. Altered Intercellular Communication

Ageing disrupts communication between cells and tissues, particularly through chronic low-grade inflammation (termed "inflammaging") and changes in cytokine signaling. Additionally, intercellular mitochondrial communication plays a regulatory role in ageing, influencing metabolic homeostasis and immune function. Dysregulation of these communication networks contributes to systemic decline and increased disease risk (Zhang et al., 2024; Li et al., 2021).

Conclusion

The nine hallmarks of ageing represent the core biological processes that underpin cellular decline and organismal ageing. Interventions targeting these mechanisms—ranging from senolytics and caloric restriction mimetics to mitochondrial protectants and stem cell therapies—are at the forefront of ageing research. Continued understanding of these pathways will be vital for developing effective strategies to promote healthy ageing and extend healthspan.

References

Dhar, P., Moodithaya, S.S. and Patil, P. (2022) ‘Epigenetic alterations—The silent indicator for early aging and age‐associated health‐risks’, Aging Medicine, 5(4). doi:10.1002/agm2.12236.

Efeyan, A., Comb, W.C. and Sabatini, D.M. (2015) ‘Nutrient-sensing mechanisms and pathways’, Nature, 517(7534), pp.302–310. doi:10.1038/nature14190.

Li, Z. et al. (2021) ‘Aging and age‐related diseases: From mechanisms to therapeutic strategies’, Biogerontology, 22(2), pp.165–187. doi:10.1007/s10522-021-09910-5.

López-Gil, L., Pascual-Ahuir, A. and Proft, M. (2023) ‘Genomic Instability and Epigenetic Changes during Aging’, International Journal of Molecular Sciences, 24(18), p.14279. doi:10.3390/ijms241814279.

Mylonas, A. and O’Loghlen, A. (2022) ‘Cellular Senescence and Ageing: Mechanisms and Interventions’, Frontiers in Aging, 3. doi:10.3389/fragi.2022.866718.

Oh, J., Lee, Y.D. and Wagers, A.J. (2014) ‘Stem cell aging: mechanisms, regulators and therapeutic opportunities’, Nature Medicine, 20(8), pp.870–880. doi:10.1038/nm.3651.