The 9 Biochemical Mechanisms of Aging

Aging is characterized by a progressive loss of physiological integrity, leading to an impairment of vital functions and a progressive increase in vulnerability until the end of existence. This “physiological deterioration” is the primary risk factor for the onset of numerous diseases such as cancer, diabetes, cardiovascular disease, and neurodegenerative disorders. In recent years, the discovery that the aging process is partly regulated by specific genetic and biochemical pathways has greatly stimulated research in the field of healthy aging, identifying the nine hallmarks common to the aging process.

The Hallmarks of ageing, Cell. 2013

The hallmarks of aging are biochemical changes that occur in the aging body and represent physiological targets that can be acted upon to control or prevent the aging process.1

The first 4 hallmarks are termed “primary” because they account for the onset of cellular damage that occurs with aging:

Genomic instability is embodied in the accumulation of DNA damage due to both exogenous factors (chemical, physical, biological agents) and endogenous (replication errors, spontaneous hydrolysis, oxidative stress) factors that progressively increase as a result of the diminished performance of the DNA duplication repair mechanisms, resulting in the accumulation of mutations that lead to aging and the onset of diseases such as cancer.2

Telomeres, produced by the enzyme telomerase, are highly repetitive sequences at the end of chromosomes that protect DNA coding sequences and act as a sort of clock controlling the number of replications a cell undergoes. Oxidative stress and a chronic inflammatory state favor premature telomere attrition, contributing to cellular aging.3

Alterations in gene expression that negatively impact fundamental functions for proper cellular maintenance: these include changes in DNA methylation patterns, histone acetylation, and chromatin remodeling, and result in increased chromosomal fragility, transcription errors, and failure to repair. In this case, oxidative stress, pollution, external factors, and alterations in the signaling of pro-inflammatory cytokines and chemokines can also contribute to epigenetic alterations.4

The loss of proteostasis is the alteration of the mechanism responsible for protein homeostasis (proper protein folding and the associated turnover), resulting in the accumulation of toxic derivatives and aggregates, which are responsible for many degenerative diseases such as Parkinson’s and Alzheimer’s. Oxidative and inflammatory stress can negatively impact the mechanisms controlling the quality of the protein balance, accelerating the aging process.5

The next 3 hallmarks are defined as “antagonistic” (compensatory) and are the direct consequence of the effects of the primary hallmarks:

Nutrient sensing mechanisms become impaired when the cell cannot recognize and respond to the available nutrients. This alteration is facilitated by various factors that support anabolic mechanisms and cellular reproduction (e.g., insulin, insulin growth factor (IGF), growth factor, mTOR). At the same time, it is counteracted by signaling related to sirtuins and AMPK and by mechanisms that mimic caloric restriction and catabolic activity. AMPK is an activator of catabolic pathways (e.g., β-oxidation of fatty acids) and suppresses metabolic mechanisms such as cholesterol and fatty acid biosynthesis.

Sirtuins are a family of seven proteins that use NAD+ as a cofactor and facilitate the activity of AMPK. They are crucial for cellular metabolism and play a key role in cellular response mechanisms to genotoxic and oxidative stress, maintaining a proper chromatin state and activating DNA repair mechanisms.6,7

Mitochondria are organelles that produce energy in the form of ATP, the fuel of all the various cellular processes. This capacity becomes impaired with aging, and inefficiencies occur in the respiratory chain that unbalance the oxidative state and promote an excessive accumulation of ROS (reactive oxygen species) and prooxidants that impair the mitochondrial DNA phospholipid membrane and damage its electrochemical balances, favoring mitochondrial DNA mutations.8-10

Senescence manifests more macroscopically at the cellular level. Senescent cells lose the ability to replicate and express pro-inflammatory mediators that are toxic to neighboring cells and cause them to become senescent (“Senescence Associated Secretory Phenotype”).11

Finally,  2 hallmarks are termed “integrative,” as they result from the summation of the effects of the primary and compensatory hallmarks and lead to the functional decline observed in the phenotype during aging:

Stem cell exhaustion is primarily caused by telomere attrition, which induces a decline in regenerative capacity, and genetic and epigenetic instabilities, which impact proper cell replication.12 Of the various bodily systems, the immune system is among the most adversely impacted by stem cell exhaustion, as lymphocytes, monocytes, and granulocytes are generated from stem cells, thus leading to a condition of immunosuppression and decreased resistance to xenobiotic attacks.13

Aging involves complex changes in intercellular communication, whether it be endocrine, neuroendocrine, or neuronal.”1

To counteract the 9 biochemical mechanisms underlying the aging process, our research studied Body 9:9 as a combination of ingredients with anti-inflammatory antioxidant action, which bolster metabolic control and the immune system, for a broad-spectrum preventive action.

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  1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217
  2. Ioannidou A, Goulielmaki E, Garinis GA. DNA Damage: From Chronic Inflammation to Age-Related Deterioration. Front Genet. 2016 Oct 25;7:187.
  3. Saretzki G. Telomeres, Telomerase and Ageing, Biochemistry and Cell Biology of Ageing Part I Biomedical Science. Subcellular Biochemistry, vol 90. Springer, Singapore
  4. Niwa T, Ushijima T. Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis. Adv Genet. 2010;71:41-56
  5. Ruano D. Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation. Front Mol Biosci. 2021 Jun 17;8:658742
  6. Efeyan, A., Comb, W. & Sabatini, D. Nutrient-sensing mechanisms and pathways. Nature 517, 302–310 (2015)
  7. Pyo IS, Yun S, Yoon YE, Choi JW, Lee SJ. Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases. Molecules. 2020 Oct 12;25 (20):4649.
  8. Amorim, J.A., Coppotelli, G., Rolo, A.P. et al. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nat Rev Endocrinol 18, 243–258 (2022).
  9. Payne BA, Chinnery PF. Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochim Biophys Acta. 2015 Nov;1847(11):1347-53.
  10. Nicolson GL. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Altern Ther Health Med. 2014 Winter;20 Suppl 1:18-25.
  11. Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol. 2021 Mar 29;9:645593.
  12. Sameri S, Samadi P, Dehghan R, Salem E, Fayazi N, Amini R. Stem Cell Aging in Lifespan and Disease: A State-of-the-Art Review. Curr Stem Cell Res Ther. 2020;15(4):362-378.
  13. Borgoni S, Kudryashova KS, Burka K, de Magalhães JP. Targeting immune dysfunction in aging. Ageing Res Rev. 2021 Sep;70:101410.


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