Aging is No.1 Risk Factor for Almost All Chronic Diseases and Death

Aging is the most significant risk factor for almost every chronic disease and for death itself. While often thought of as an inevitable, passive process, aging is increasingly understood as an active, biological phenomenon driven by identifiable mechanisms.

Among the most profound insights in modern biomedicine is the recognition that the same underlying biological processes that drive aging also give rise to most chronic diseases, from cardiovascular disease to cancer and neurodegeneration like Alzheimer’s disease.

The Hallmarks of Aging

In 2013, López-Otín and colleagues introduced a conceptual framework known as the "Hallmarks of Aging," explained the basis of aging. They identified nine key processes contributing to age-related decline.

In 2023, the same group expanded this list to 12 Hallmarks of Aging, providing a more comprehensive picture of the aging process and its links to disease [1] . Dysbiosis, disabled macroautophagy and chronic inflammation are the new members of the list.

The expanded 12 hallmarks include:

1. Genomic instability

2. Telomere attrition

3. Epigenetic alterations

4. Loss of proteostasis

5. Disabled macroautophagy

6. Deregulated nutrient sensing

7. Mitochondrial dysfunction

8. Cellular senescence

9. Stem cell exhaustion

10. Altered intercellular communication

11. Chronic inflammation

12. Dysbiosis

These hallmarks do not function independently. Instead, they interact in complex feedback loops, contributing to the progressive breakdown of cellular and tissue integrity, increasing vulnerability to disease.

Rather than causing disease in a direct, linear way, aging creates a biological environment in which disease thrives. For example, genomic instability leads to mutations that promote cancer, chronic inflammation contributes to atherosclerosis and neurodegeneration, and stem cell exhaustion limits tissue repair, increasing the risk of organ failure. These hallmarks form the biological foundation for the major diseases of aging.

Top 3 Age-Related Diseases Linked to Aging Biology

1. Cardiovascular Disease (CVD)

CVD is the leading cause of death globally, accounting for an estimated 17.9 million deaths each year, which represents 32% of all global deaths [2] . Its incidence rises sharply with age. Hallmarks such as chronic inflammation, mitochondrial dysfunction, and telomere attrition contribute to endothelial dysfunction, arterial stiffening, and plaque formation.

Additionally, dysregulated nutrient sensing and cellular senescence promote metabolic disturbances that worsen cardiovascular outcomes [3]

2. Cancer

Cancer risk increases dramatically with age, partly due to genomic instability, epigenetic alterations, and loss of proteostasis. These processes allow damaged cells to evade repair mechanisms and proliferate uncontrollably.

Cellular senescence, while initially a protective response to damage, can fuel tumor growth via pro-inflammatory secretions from senescent cells [4].

3. Neurodegenerative Diseases (e.g., Alzheimer’s Disease)

Neurodegenerative disorders like Alzheimer’s are strongly age-associated. Mitochondrial dysfunction, loss of proteostasis, and disabled macroautophagy lead to the accumulation of toxic proteins in neurons.

Chronic inflammation, another hallmark, disrupts neuronal communication and plasticity, has been increasingly linked to brain aging and cognitive decline [5].

Geroscience: Targeting Aging to Prevent Multiple Diseases

Age-related diseases share more than demographic overlap. They share the same biological root, aging, as the common denominator. This insight has given rise to geroscience, a field that seeks to delay, prevent, or even reverse multiple diseases by targeting the mechanisms of aging itself [6]. The growth has been promising and the search of longevity is not far away.

Let’s dive into deeper connection in between aging and chronic diseases. Rather than fighting one disease at a time, geroscience aims to extend healthspan, the period of life spent free of disease by intervening upstream, from the root-causes of diseases.

For instance, drugs like rapamycin and metformin, as well as lifestyle interventions like caloric restriction and exercise, have shown promise in targeting nutrient-sensing pathways, autophagy, and chronic inflammation.

Metformin, a common antidiabetic drug, is being investigated in geroscience for its potential to target multiple hallmarks of aging and extend healthspan by modulating nutrient-sensing pathways and reducing systemic inflammation [7] .

The Paradigm Shift in Medicine

As the global population ages, the shift of paradigm in medicine being witnessed as economic and human burden of chronic disease continues to mount. Recognizing aging as the central driver of these diseases offers a unifying strategy for prevention.

Instead of isolated treatments for heart disease, cancer, or dementia, targeting the biology of aging offers a single intervention point with the potential to prevent many conditions simultaneously. Ultra-personalised and precision approach in medicine are the paramount of success in keeping the age related diseases at bay.

Conclusion: Toward Longer, Healthier Lives

In summary, aging is not merely a backdrop for disease manifestation but it is the primary risk factor driving nearly all chronic illnesses and mortality. The 12 hallmarks of aging provide a biological blueprint for understanding this relationship and offer promising targets for intervention.

By shifting our medical focus from disease management to aging biology, we have the potential not only to extend lifespan but to improve the healthspan of those added years. Thus, to live longer, to live better is no longer a hope but a reality.

References:

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

[2] World Health Organization. Cardiovascular diseases (CVDs). WHO https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (2021).

[3] North, B. J. & Sinclair, D. A. The intersection between aging and cardiovascular disease. Circ. Res. 110, 1097–1108 (2012).

[4] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

[5] Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L. & Bohr, V. A. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. **15**, 565–581 (2019).

[6] Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S. & Sierra, F. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014).

[7] BArzilai, N., Crandall, J. P., Kritchevsky, S. B. & Espeland, M. A. Metformin as a tool to target aging. Cell Metab. 23, 1060–1065 (2016).