The Evolution of the Hallmarks of Aging

Abstract

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the "hallmarks of aging," i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging - the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called "layers of aging." A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike "from the inside" of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism "from the outside," i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control - e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.

Keywords: aging; bilaterians; evolution; geroscience; metacellular aging; unicellular aging.

FIGURE 1

The 9 “synthetic” and the 20 “analytic” hallmarks of aging as originally proposed in López-Otín et al. (2013). The wheel in the original figure proposes only 9 hallmarks of aging, but the text distinguishes more. The present article is based on the detailed hallmarks, which are represented here as an extension of the wheel.

FIGURE 2

Phylogeny used for the investigation of mechanisms of aging. Circles are clades. Their names are in white. Current species represented in each clade are as remote as possible from humans phylogenetically and hypothetically as close as possible to the early species where the clade originated. The tree of life is also represented on the figure.

FIGURE 3

The evolution of the hallmarks of aging. The 20 layers of aging are represented in the order of appearance in evolution from cellular organisms to bilaterians (from the earliest at the bottom to the latest at the top). The colors of the layers correspond to the original 9 “synthetic” hallmarks of aging. Clades are represented in the gray zones along with corresponding model organisms. The sets of layers of unicellular aging and metacellular aging are represented.