All Roads Lead to Aging
In 2013, López-Otín and a team of researchers published The Hallmarks of Aging based on the conceptual framework of “The Hallmarks of Cancer”. Hanahan and Weinberg’s categorization of cancer traits impulsed the field and facilitated its accessibility. The aging hallmarks meet these criteria: (1) manifest during normal aging; (2) its experimental aggravation should accelerate aging; and (3) its experimental amelioration should delay the normal aging process and hence increase healthy lifespan (López-Otín et al., 2013).
Every nucleus in all cells of the human body contains the genome—the complete set of DNA. And DNA contains the information required to build the human body; however, the genome’s integrity and stability is continuously challenged by external biological, chemical, and physical sources like radiation and pollutants as well as by internal threats, including DNA replication errors and free radicals. As the body ages, it accumulates DNA damage and imperfect repair.
Cumulative DNA damage affects telomeres—DNA sequences that protect the ends of chromosomes from damage and prevent their misidentification for broken DNA strands. Necessary cell division shortens telomeres, which ultimately causes its exhaustion associated with age-related diseases, aging, and mortality.
The epigenome regulates genomic functioning. Alterations such as methylation of DNA and histones affect all cells and tissues throughout life and can induce epigenetic changes associated with normal and premature aging.
Genes encode proteins and proteins direct cell function. During aging, the functional fold of proteins is altered as they are damaged by regular cellular processes. Misfolded proteins are then dysfunctional and may harm the body. As proteostasis—protein balance—is lost, it contributes to the development of some age-related diseases such as Alzheimer’s.
Deregulated Nutrient Sensing
Anabolic signaling—communication needed for molecule construction—damages cells and alters nutrient-sensing molecules and pathways, thereby accelerating aging. Reduced caloric intake and drugs like rapamycin decreases nutrient signaling and improves longevity in some species.
Mitochondria produce most of the energy needed by the cell. As cells and organisms age, the efficacy of the mitochondria diminishes, which is associated with fatigue and multiple chronic diseases.
Cells that no longer divide are senescent. Telomere shortening and other aging-associated stimuli induce senescence. Cellular senescence is protective against cancer and prevents proliferation of damaged cells. But as the body ages and becomes less efficient, it accumulates senescent cells that secrete harmful molecules and contribute to aging.
Stem Cell Exhaustion
Stem cells are critical to repair organs and tissues, however, their replication and regenerative abilities decline with age. As stem cells get exhausted, they lead to detrimental conditions such as immunosenescence—decline of the innate and adaptive immune system.
Altered Intercellular Communication
The ability to relay information and instructions from one cell to another, for instance, at the neuronal and hormonal level contribute to declining tissue health when it is disturbed by aging. A salient alteration is inflammaging—chronic, low-grade inflammation associated with multiple diseases. Additionally, aging-related changes in one tissue can lead to aging of other tissues, and senescent cells can induce senescence in neighboring cells—phenomena known as contagious aging.
The definition of the hallmarks is an impressive indication that aging is an intricate process elucidated by a core collection of interconnected principles. Effectively targeting aging from a myriad of biomedical approaches will enable humanity to live healthier, longer lives.
López-Otín, Carlos, et al. “The Hallmarks of Aging.” Cell, vol. 153, no. 6, 2013, pp. 1194–1217, https://doi.org/10.1016/j.cell.2013.05.039.