Abstract
Throughout life, organisms are exposed to various exogenous and endogenous factors that cause DNA damages and somatic mutations provoking genomic instability. At a young age, compensatory mechanisms of genome protection are activated to prevent phenotypic and functional changes. However, the increasing stress and age-related deterioration in the functioning of these mechanisms result in damage accumulation, overcoming the functional threshold. This leads to aging and the development of age-related diseases. There are several ways to counteract these changes: (1) prevention of DNA damage through stimulation of antioxidant and detoxification systems, as well as transition metal chelation; (2) regulation of DNA methylation, chromatin structure, non-coding RNA activity and prevention of nuclear architecture alterations; (3) improving DNA damage response and repair; (4) selective removal of damaged non-functional and senescent cells. In the article, we have reviewed data about the effects of various trace elements, vitamins, polyphenols, terpenes, and other phytochemicals, as well as a number of synthetic pharmacological substances in these ways. Most of the compounds demonstrate the geroprotective potential and increase the lifespan in model organisms. However, their genome-protecting effects are non-selective and often are conditioned by hormesis. Consequently, the development of selective drugs targeting genome protection is an advanced direction.
Highlights
The accumulation of genome damage and somatic mutations leading to genome instability are important determinants and hallmarks of aging [1,2,3]
The consequences of the failure of mechanisms to maintain genome stability are vividly illustrated by the pathological patterns of numerous accelerated asging syndromes that are caused by mutations in DNA repair genes and nuclear architecture maintenance genes [6,7,8,9,10]
Mutations in genes of a nuclear lamina cause premature aging syndromes called laminopathies [90,91]. It affects the speed of telomere shortening, the activity of genes and signaling pathways, the organization of chromatin, and DNA methylation patterns [2,89]
Summary
The accumulation of genome damage and somatic mutations leading to genome instability are important determinants and hallmarks of aging [1,2,3]. The frequency of DNA damage and somatic mutations in tissues of animals and humans increases, genomic instability arises, which is expressed in a burst of point mutations, breaks, Int. J. Mutations in genes of a nuclear lamina cause premature aging syndromes called laminopathies (including Hutchinson–Gilford syndrome) [90,91] It affects the speed of telomere shortening, the activity of genes and signaling pathways (including those associated with DNA damage response and aging), the organization of chromatin, and DNA methylation patterns [2,89]. Increasing genomic instability leads to a change in the transcription of vital genes, disruption of cellular metabolism, and causes cellular senescence This leads to the accumulation of dysfunctional cells and genetic heterogeneity, a disruption of the regenerative potential, and physiological functions of tissues [3]. Persistent DNA damage response induces p21 and p16 cyclin-dependent kinase inhibitors and activation of the pRB retinoblastoma tumor suppressor pathway arresting the progress of the cell cycle [126,127]
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