Theories and Mechanisms of Aging
Humanity has undoubtedly made amazing strides in civilization, knowledge, and technology; nonetheless, the mysteries that control the human lifespan have yet to be unraveled. Medical tests, treatments, and innovations allow people to live longer than before, but age-related changes and conditions continue to exist, and are even exacerbated in some cases. Several biological theories of aging have emerged, with two distinct categories: the programmed theories and the damage/error theories. Programmed theories suggest aging is a factor of time, like the process that regulates growth and development in childhood. As a result, theories in this category involve genetic expression, maintenance of biological systems, and repair/defense responses. On the other hand, the damage/error theories advocate environmental factors that damage organisms at varying degrees is the core cause of aging.1
One of the forerunners of the programmed theories is the immunological theory of aging. Aging affects both the innate and adaptive branches of the immune system. Several of the most critical components of immune cell function, including phagocytosis, chemotaxis, and cytotoxicity, are altered by aging’s course. Invading organisms are typically sensed by immune cells such as innate macrophages and neutrophils, which activate NF-κB to secrete proinflammatory molecules, produce effector molecules, and alert additional immune cells.2 As we age, control over this highly regulated process is lost, causing a decrease in proinflammatory molecules, in addition to inducing continuous molecular injury. Additionally, the production of chemokines and cytokines by NK cells gradually slows, increasing the susceptibility of older organisms to infections and cancers.2 This maintains a vicious, self-sustaining loop of deterioration, which only gets worse with time. T-cells are the only immune cells capable of recognizing and responding to each unique antigenic epitope. With aging, these are sub-optimally activated, diminishing the overall adaptive immune and memory response.3
One of the damage/error theories, the wear and tear theory proposes aging is simply a result of the body’s gradual deterioration. This theory is perhaps the one most strongly derived from “common sense,” since it suggests living organisms, like inanimate objects, will “wear out” over time with repeated use and increased stress.4 Supporting this theory is the visual observation that both internal and external bodily organs noticeably deteriorate over time, regardless of the individual’s lifestyle. Additionally, our nerve cells are largely not replaced as we age; therefore, it seems plausible that the gradual loss of these cells inevitably leads to decreased functionality. Despite the popularity of this theory before the advent of modern medicine, most researchers of today argue that the theory is outdated, citing examples such as the transition from infancy to childhood, where development happens rather than decline.4
Another theory in the damage/error category is the free radical theory, which proposes reactive oxygen species damage the macromolecular components of living cells, thereby decreasing the organism’s lifespan. In theory, mitochondrial respiration supports the transformation of diatomic oxygen atoms (O2) into water (H2O) through a four-electron reduction. However, like all biological processes, this cascade is imperfect, and when O2 loses only one electron, it becomes O-2; when it only loses two electrons, it becomes H2O2. In the presence of free transition metals such as iron and copper, O-2 and H2O2 can generate the extremely reactive hydroxyl radical OH, which is ultimately responsible for the oxidative destruction of biomolecules.5 Lipid peroxidation, which is when a lipid hydroperoxyl radical takes a hydrogen atom from the double bond of a nearby unsaturated lipid, relies on the production of free radicals that are chemically similar to the molecular species in radiation. As follows, this process is almost one-tenth as damaging as ionizing radiation and can initiate membrane damage and rupture.6,7 Additionally, lipid peroxidation can induce ferroptosis, a form of cell death caused by iron toxicity.7 Oxidative effects on nucleic acids lead to DNA oxidation, which has been associated with developmental defects, including mental retardation, Cockayne’s syndrome, and childhood death.8
Overall, while multiple theories of aging have been proposed, there is no solid consensus on this discussion. Each of the theories has supporting evidence, and many overlap with each other. Increasing our understanding of the aging process may promote not only successful aging but also increased understanding of disease and mechanisms of therapeutic action.
References
- Jin, Kunlin. “Modern Biological Theories of Aging.” Aging and Disease, vol. 1, no. 2, Aug. 2010, pp. 72–74. PubMed Central, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995895/
- Fulop, Tamas, et. al. “On the Immunological Theory of Aging.” Interdisciplinary Topics in Gerontology and Geriatrics, edited by L. Robert and T. Fulop, vol. 39, S. Karger AG, 2014, pp. 163–76. DOI.org (Crossref), https://doi.org/10.1159/000358904
- Cano, R. Luz Elena, and H. Damaris E. Lopera. “Introduction to T and B Lymphocytes.” Autoimmunity: From Bench to Bedside [Internet], El Rosario University Press, 2013. www.ncbi.nlm.nih.gov, https://www.ncbi.nlm.nih.gov/books/NBK459471/
- Sattaur, Zahra, et. al. “Wear and Tear Theory of Aging.” Essays in Developmental Psychology, Jan. 2020, https://nsuworks.nova.edu/cps_facbooks/732
- Beckman, Kenneth B., and Bruce N. Ames. “The Free Radical Theory of Aging Matures.” Physiological Reviews, vol. 78, no. 2, Apr. 1998, pp. 547–81. DOI.org (Crossref), https://doi.org/10.1152/physrev.1998.78.2.547