Aging has been characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 to conceptualize the essence of biological aging and its underlying mechanisms. The following three premises for the interconnected hallmarks have been proposed:
"their age-associated manifestation" "the acceleration of aging by experimentally accentuating them" "the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them"
Overview Over time, almost all living organisms experience a gradual and irreversible increase in senescence and an associated loss of proper function of the bodily systems. As aging is the primary risk factor for major human diseases, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases, it is important to describe and classify the types of changes that it entails. After a decade, the authors of the heavily cited original paper updated the set of proposed hallmarks in January 2023. In the new review, three new hallmarks have been added: macroautophagy, chronic inflammation and dysbiosis, totaling 12 proposed hallmarks. The nine hallmarks of aging of the original paper are grouped into three categories as below: Primary hallmarks (causes of damage)
Genome instability Telomere shortening (or telomere attrition) Epigenetic alterations Loss of proteostasis macroautophagy Antagonistic hallmarks (responses to damage)
Deregulated nutrient sensing Mitochondrial dysfunction Cellular senescence Integrative hallmarks (culprits of the phenotype)
Stem cell exhaustion Altered intercellular communication chronic inflammation dysbiosis Primary hallmarks are the primary causes of cellular damage. Antagonistic hallmarks are antagonistic or compensatory responses to the manifestation of the primary hallmarks. Integrative hallmarks are the functional result of the previous two groups of hallmarks that lead to further operational deterioration associated with aging. There are also proposed further hallmarks or underlying mechanisms that drive multiple of these hallmarks.
The hallmarks Each hallmark was chosen to try to fulfill the following criteria:
manifests during normal aging; experimentally increasing it accelerates aging; experimentally amending it slows the normal aging process and increases healthy lifespan. These conditions are met to different extents by each of these hallmarks. The last criterion is not present in many of the hallmarks, as science has not yet found feasible ways to amend these problems in living organisms.
Genome instability
Proper functioning of the genome is one of the most important prerequisites for the smooth functioning of a cell and the organism as a whole. Alterations in the genetic code have long been considered one of the main causal factors in aging. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. Abnormal chemical structures in the DNA are formed mainly through oxidative stress and environmental factors. A number of molecular processes work continuously to repair this damage. Unfortunately, the results are not perfect, and thus damage accumulates over time. Several review articles have shown that deficient DNA repair, allowing greater accumulation of DNA damages, causes premature aging; and that increased DNA repair facilitates greater longevity.
Telomere shortening
Telomeres are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. They protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the ends of the DNA strand for a double strand break. Telomere shortening is associated with aging, mortality and aging-related diseases. Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging. Leonard Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase. Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. This is useful when uncontrolled cell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary. An enzyme called telomerase elongates telomeres in gametes and stem cells. Telomerase deficiency in humans has been linked to several aging-related diseases related to loss of regenerative capacity of tissues. It has also been shown that premature aging in telomerase-deficient mice is reverted when telomerase is reactivated. The shelterin protein complex regulates telomerase activity in addition to protecting telomeres from DNA repair in eukaryotes.
Epigenomic alterations
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