Muller’s ratchet as a mechanism of frailty and multimorbidity

Abstract

Mutation accumulation has been proposed as a cause of senescence. In this process, both constitutional and recurrent mutations accumulate gradually and differentially among differentiating cells, tissues and organs, in relation to stage and age, analogous to Mullers ratchet in asexually reproducing organisms. Latent and cascading deleterious effects of mutations might initiate steady \"accumulation of deficits\" in cells, leading to cellular senescence, and functional decline of tissues and organs, and ultimately manifest as frailties and disease. We investigated a few of these aspects in cell populations through modeling and simulation using the Moran birth-death process, under varied scenarios of mutation accumulation. Our results agree with the principle of Mullers ratchet. The ratchet speed in a given tissue depends on the population size of cells, mutation rate, and selection coefficient. Additionally, deleterious mutations seem to rapidly accumulate particularly early in the life-course, during which the rate of cell division is high, thereby exerting a greater effect on cellular senescence. The speed of the ratchet afterward varies greatly between cells nested in tissues and tissues within organs due to heterogeneity in the life span and turnover rate of specific cell types. Importantly, the ratchet accelerates with age, resulting in a synergistic fitness decay in cell populations. We extend Fishers average excess concept and rank order scale to interpret differential phenotypic effects of mutation load in a given tissue. We conclude that classical evolutionary genetic models could explain partially, the origins of frailty, subclinical conditions, morbidity and health consequences of senescence.\n\nSignificanceFrailty is defined as physiological and functional decline of organs and organ systems, due to deficit accumulation from stochastic damages within the organism with advanced age. Equivalently, with age, both constitutional and somatic mutations accumulate gradually and differentially among cells, cell lineages, tissues, and organs. Since most mutations are deleterious, accumulation of random and recurrent mutations could create a \"load,\" on the genome and contextually express in the epigenome and phenotype spaces. Here we extend Mullers ratchet principle to explain frailty and multi-morbidity using the Moran model and simulations. Our results agree with the Mullers ratchet principle. We emphasize the need for considering cumulative effects of the entire spectrum of mutations for explaining the origin of frailty, sub-clinical conditions, and morbidity.