Mitigating age-related somatic mutation burden

Abstract

Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo, random somatic mutations as a cause of aging.

Keywords: aging; cancer; chromatin organization; clonal hematopoiesis; germline versus somatic genome; somatic mutations.

Figure 1.. Germline and somatic mutations have different trajectories.

Mutations in the germline of one of the parents end up in all somatic cells of the offspring, albeit in only one allele. Postzygotic somatic mutations can occur at any stage during embryogenesis, development, and aging. Some mutations, especially when occurring early during development, can become clonally amplified and eventually comprise a significant fraction of the somatic cells, depending on the tissue. Figure was created with BioRender.com.

Figure 2.. Exogenous and endogenous genotoxic sources lead to a large variety of DNA lesions.

Lesions include DNA double- and single-strand breaks, alkylating lesions, oxidative base modifications, and helix-distorting and bulky lesions. During DNA replication or recombination, single nucleotide variants (SNVs) or larger structural variants (SVs) can occur. SVs are more frequent and can alter the gene sequence and thus affect gene function. SNVs can have more detrimental effects as they can alter the genome structure. Figure was created with BioRender.com.

Figure 3.. The germline perpetuates the genetic information indefinitely, while the soma only needs to be maintained for one generation.

Germline genomes have by orders of magnitude lower mutation rates than somatic cells. They use accurate DNA repair mechanisms and highly effective gamete selection for the most stable genomes to be inherited. Thus germline genomes could be maintained over hundreds of millions of years in a continuous line. The somatic genome maintenance mechanisms only need to support the functionality of genomes for as long as the soma contributes to evolutionary fitness. This contribution typically vanishes ones the next generation is able to carry on the gene pool. Consequently, the requirement for efficient and accurate genome maintenance in somatic tissues is lower than in the germline. Somatic DNA repair is insufficient for indefinite maintenance of the soma. Figure was created with BioRender.com.

Figure 4.. Sources of improved genome maintenance mechanisms.

Long-lived species such as some whales, the naked mole rat or a range of bat species, could provide mechanisms of improved somatic genome maintenance mechanisms that could potentially be adopted. Extremophiles such as tardigrades or Deinococcus radiodurans have been selected to withstand extraordinarily high levels of genotoxic stress in their habitats. Some of their mechanisms might be transferred to human cell types. The germline has far reduced mutation rates than somatic cells in humans and might thus harbor endogenous regulatory programs of DNA repair gene expression that could be employed to improve genome repair in somatic cells. The elimination of genomically compromised cells is an important selection mechanisms against instable and potentially dysfunctional or even harmful cells. Figure was created with BioRender.com.