Hallmarks of Aging

What Are the Hallmarks of Aging?

Aging is a natural and time-dependent decline in body function due to alterations at the molecular and cellular levels that leads to changes in the function of the cardiovascular system, the brain, the digestive system, the bladder and urinary tract, the muscles, joints, and muscles, the eyes and ears, the teeth, and the skin. Changes in body weight and sexuality are also observed.  

The molecular and cellular changes responsible for these physiological declines have been grouped under the name hallmarks of aging [1].

Hallmarks of Aging

1- Genomic instability

Our DNA integrity and stability are constantly confronted with external physical, chemical, and biological damaging factors, and internally through reactive oxygen species (ROS) and DNA replication errors. These damaging effects result in DNA mutations, chromosomal aberrations, and telomere shortening that lead to genomic instability responsible for diseases such as cancer [2].

However, during evolution, organisms developed DNA repair mechanisms that ensure genomic stability through the repair of DNA mutations and the maintenance of telomere length and appropriate chromosomal segregation.  Unfortunately, these repair mechanisms are severely affected by age.

2- Stem Cell Exhaustion

Within tissues and organs of the body, populations of stem cell-like cells known as adult stem cells, or adult tissue-specific stem cells maintain and repair tissues and organs throughout the life of an individual.

However, as we age, these populations of cells start to deplete due to several causes that can act individually or collectively such as DNA damage, proteostasis, epigenetics, telomere shortening, mitochondria dysfunction, and cellular senescence [3].

3- Telomere Attrition

During aging, a shortening of telomeres-specialized chromatin structures that are found at the end of chromosomes leads to gene erosion and chromosomal aberrations that result in functional inactivation, death, or senescence of cells.

For instance, the loss-of-function of Shelterin, a protein complex that protects telomeres and promotes telomerase activity, has been shown to accelerate aging and decrease tissue regeneration [4].

4- Loss of Proteostasis

As products of DNA transcription and RNA translation, proteins are molecules that are involved in all functional activities within the cells. However, when proteins are generated, they must pass a quality control test that relies on checking their synthesis, folding, and degradation. This process is known as protein homeostasis or proteostasis.

Unfortunately, this process is also affected with age leading to abnormal folding, toxic aggregation, and accumulation of damaged proteins, that result in cellular damage and tissue dysfunction [5].

5- Alteration in Mitochondria Function

A theory proposed that elevated ROS are associated with a decline in the integrity of mitochondria [6]. Reactive oxygen species (ROS) that are produced by the mitochondria can induce oxidative damage to the mitochondria resulting in increased aging [7].

Accelerated aging was also proposed to be associated with a reduction of mitochondria energy flow, known as bioenergetics, due to a decline in the renewal of mitochondrial number and size (Biogenesis) with age [8].

6- Cellular Senescence

Cellular senescence is associated with cells that stopped dividing without entering a programmed cell death. This cellular arrest in growth is associated with non-telomeric DNA damage and shortening of the telomeres in senescent cells.

The role of senescent cells in aging is linked with their “senescence-associated secretory phenotype” characterized by the secretion of pro-inflammatory cytokines and matrix metalloproteinases that promote aging [9].

7-Epigenetic Alterations

During the process of aging, DNA is subject to epigenetic changes such as acetylation, methylation, post-translational modifications of histones, and chromatin remodeling. These changes control the expression of longevity genes. For instance, progeroid cells (faster-aging cells) exhibit DNA methylation patterns and histone modifications that mostly recapitulate those found in normal aging [10].

8- Alterations in Nutrients’ sensing

Nutrient sensing is the cell’s capacity to detect the levels of nutrients such as glucose and metabolites. The insulin and IGF-1 signaling pathways, growth hormone (GH), and the AMP-activated kinase (AMPK) are major nutrient-sensing pathways.

Interestingly, several studies showed a correlation between longevity and the reduction in growth hormone (GH) and in the IGF-1 signaling pathway [11] [12]. Through the activation of several metabolic pathways, AMPK has also been proposed to promote healthy aging [13].

9- Inflammation

Several studies have identified a link between chronic inflammation and longevity [14]. Although inflammation, such as acute inflammation is an essential event in immune response and tissue homeostasis, chronic inflammation has been associated with chronic diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer.

These diseases are the main causes of bad quality of life, and death, and therefore, significantly reduce individuals’ lifespan. A group of genes named Conserved Transcriptional Response to Adversity (CTRA) appears to play a key role in linking chronic inflammation and longevity [15].


Although aging is a complex natural phenomenon that involves molecular, metabolic, and cellular alterations of tissues and organs, it is still possible to slow it down through healthy diets such as epigenetic and restrictive diets, and physical activity through frequent walks and exercise.


[1] López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M. and Kroemer, G., 2013. The hallmarks of aging. Cell153(6), pp.1194-1217.

[2] Hoeijmakers, J.H., 2009. DNA damage, aging, and cancer. New England Journal of Medicine361(15), pp.1475-1485.

[3] Oh, J., Lee, Y.D. and Wagers, A.J., 2014. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature medicine20(8), pp.870-880.

[4] Martínez, P. and Blasco, M.A., 2010. Role of shelterin in cancer and aging. Aging cell9(5), pp.653-666.

[5] Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C.M. and Stefani, M., 2002. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. nature416(6880), pp.507-511.

[6] Harman, D., 1972. Free radical theory of aging: dietary implications. The American journal of clinical nutrition25(8), pp.839-843.

[7] Edgar, D., Shabalina, I., Camara, Y., Wredenberg, A., Calvaruso, M.A., Nijtmans, L., Nedergaard, J., Cannon, B., Larsson, N.G. and Trifunovic, A., 2009. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell metabolism10(2), pp.131-138.

[8] Sahin, E. and DePinho, R.A., 2012. Axis of ageing: telomeres, p53 and mitochondria. Nature reviews Molecular cell biology13(6), pp.397-404.

[9] Rodier, F. and Campisi, J., 2011. Four faces of cellular senescence. The Journal of cell biology192(4), pp.547-556.

[10] Pollina, E.A. and Brunet, A., 2011. Epigenetic regulation of aging stem cells. Oncogene30(28), pp.3105-3126.

[11] Barzilai, N., Huffman, D.M., Muzumdar, R.H. and Bartke, A., 2012. The critical role of metabolic pathways in aging. Diabetes61(6), pp.1315-1322.

[12] Kenyon, C.J., 2010. The genetics of ageing. Nature464(7288), pp.504-512.

[13] Alers, S., Löffler, A.S., Wesselborg, S. and Stork, B., 2012. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Molecular and cellular biology32(1), pp.2-11.

[14] Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., Ferrucci, L., Gilroy, D.W., Fasano, A., Miller, G.W. and Miller, A.H., 2019. Chronic inflammation in the etiology of disease across the life span. Nature medicine25(12), pp.1822-1832.

[15] Cole, S.W., 2019. The conserved transcriptional response to adversity. Current opinion in behavioral sciences28, pp.31-37.

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