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Review
, 36 (3), 282-92

Aging Genomes: A Necessary Evil in the Logic of Life

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Review

Aging Genomes: A Necessary Evil in the Logic of Life

Jan Vijg. Bioessays.

Abstract

Genomes are inherently unstable because of the need for DNA sequence variation as a substrate for evolution through natural selection. However, most multicellular organisms have postmitotic tissues, with limited opportunity for selective removal of cells harboring persistent damage and deleterious mutations, which can therefore contribute to functional decline, disease, and death. Key in this process is the role of genome maintenance, the network of protein products that repair DNA damage and signal DNA damage response pathways. Genome maintenance is beneficial early in life by swiftly eliminating DNA damage or damaged cells, facilitating rapid cell proliferation. However, at later ages accumulation of unrepaired damage and mutations, as well as ongoing cell depletion, promotes cancer, atrophy, and other deleterious effects associated with aging. As such, genome maintenance and its phenotypic sequelae provide yet another example of antagonistic pleiotropy in aging and longevity.

Keywords: DNA damage; DNA epimutations; DNA mutations; DNA repair; aging; evolution.

Conflict of interest statement

The author has declared no conflict of interest.

Figures

Figure 1
Figure 1
The two-edged sword of genome maintenance. All organisms are continuously exposed to endogenous and exogenous sources of DNA damage. Errors during the processing of that damage by genome maintenance systems lead to inevitable and irreversible DNA mutations. In germ cells these mutations drive evolutionary change. In somatic cells of multicellular organisms these same mutations could be a cause of aging.
Figure 2
Figure 2
The major DNA repair systems in mammalian cells. Removal of the many spontaneously induced DNA lesions is the core component of genome maintenance. Each of the pathways involved continuously searches the genome for damage, which after confirmation is subsequently removed with the correct strand(s) restored.
Figure 3
Figure 3
The dual nature of genome maintenance. At early age, when mechanisms, such as apoptosis and cellular senescence, prevent cancer, genome maintenance is beneficial. The price to be paid later includes a loss of functional cells, increased numbers of senescent cells, and cumulative somatic mutations.
Figure 4
Figure 4
Single-cell analysis is required for detecting low-abundance, random mutations. The A>G mutation (red check mark in the cell) can only be distinguished from sequencing errors after single-cell, whole genome amplification. It now shows up in ~50% of the reads (one mutated allele). Single-nucleotide polymorphisms on the other hand can be readily detected by sequencing bulk DNA from the entire cell population. The heterozygous T>C SNP is present in both the amplified single-cell genome and the unamplified bulk DNA genome in ~50% of the reads.
Figure 5
Figure 5
Hypothetical model for increased heterogeneity of cellular genotypes in tissues during aging. The increased loads of random mutations and epimutations are hypothesized to cause loss of function (increased red color). They also cause tumors (hatched cells). Simultaneously, cellular responses to DNA damage would lead to increased senescent cells (blue) and cell depletion due to apoptosis.

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