No Time to Age: Uncoupling Aging from Chronological Time

Abstract

Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal soma, which ages and dies. In this review, we describe the germline as clock-free and the soma as clock-bound and discuss aging with respect to three DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks. We further describe how germline factor reprogramming might be used to slow the rate of aging and potentially reverse it by causing the clocks to tick backward. Therefore, reprogramming may eventually lead to therapeutic strategies to treat degenerative diseases by altering aging itself, the one condition common to us all.

DNA methylation meta-analysis confirms the division of the genome into two functional groups

“…Interest in DNA methylation has led to the emergence of a large number of studies devoted to genome methylation and the generation of accessible databases, allowing it to be used for testing different points of view on the aging processes. Currently, there are many theories that give their explanation of the causes of aging, but there is no unanimous opinion on the problem [12,13,14]. We share the viewpoint that in the case of a multicultural organism, aging is always accompanied by a decrease in the resources required by its cells for repair and tissue regeneration [15,16,17, 18].…”

How to Slow down the Ticking Clock: Age-Associated Epigenetic Alterations and Related Interventions to Extend Life Span

“…At present, it is hypothesized that partial reprogramming results in a continuously decreasing epigenetic age before cell identity is lost [355]. While a linear decrease in epigenetic age was observed within the first 20 days of fibroblast reprogramming, full pluripotency was only reached after 28 days [356]. This raises hope that the loss of cell identity and the reset of the epigenetic clock can be uncoupled, thus allowing for rejuvenation without increased risk for tumor formation.…”

Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research

“…However, none of the five neoplastic properties are unique to malignant cells, and not even to benign cells, as these cellular properties are developed along with evolution from prokaryotic to eukaryotic and then to multicellular organisms. In other words, the genomes of animals (including the human being) encode these cellular properties and thus do not need mutations for their occurrence [62,287,288]: First, a normal human body consists of not only somatic cells, which are mortal and may undergo symmetric division, but also germline cells that are immortal and undergo asymmetric division [289,290]. Actually, there are some plants and animals that are immortal as well [290,291].…”