How can aging be reversed? Exploring rejuvenation from a damage-based perspective

Abstract

Advanced age is associated with accumulation of damage and other deleterious changes and a consequential systemic decline of function. This decline affects all organs and systems in an organism, leading to their inadaptability to the environment, and therefore is thought to be inevitable for humans and most animal species. However, in vitro and in vivo application of reprogramming strategies, which convert somatic cells to induced pluripotent stem cells, has demonstrated that the aged cells can be rejuvenated. Moreover, the data and theoretical considerations suggest that reversing the biological age of somatic cells (from old to young) and de-differentiating somatic cells into stem cells represent two distinct processes that take place during rejuvenation, and thus they may be differently targeted. We advance a stemness-function model to explain these data and discuss a possibility of rejuvenation from the perspective of damage accumulation. In turn, this suggests approaches to achieve rejuvenation of cells in vitro and in vivo.

Keywords: aging; biomarkers of aging; partial reprogramming; regeneration; rejuvenation.

FIGURE 1

Facts and theories of aging. There are important experimental observations (facts) in the field of aging as well as many proposed theories to explain the aging process. They offer insights into particular aspects of the aging process, but require integration to better describe the complexity of aging

FIGURE 2

Aging from an entropy perspective. Upper: Analogy of aging to a chemical oscillation structure. Humans continuously exchange entropy with the environment by exchanging materials and energy in order to maintain the ordered biological structure. A restricted exchange of substances leads to aging. Lower: Further damage is caused by limits to obtain energy. The inability to take in substances disrupts functions and limits the ability to consume energy and repair damage, and the existing damage then makes biological systems produce more damage

FIGURE 3

Antagonistic pleiotropy. The antagonistic pleiotropy (AP) theory states that certain alleles and genes that are beneficial in early life can be detrimental in later life, causing aging. However, the great majority of genes exhibit AP features, and this happens regardless of whether the organism containing these genes ages or not. We point out that the beneficial features of AP genes are represented by their functions, whereas the deleterious features are represented by damage generated because of these functions. This damage accumulates over time, leading to the appearance of the damaging effects of genes in late life. However, genes are not equal in their AP properties since in the extreme cases their beneficial effects may span most of the lifespan or be confined to a certain stage of development, and their deleterious effects may significantly contribute to the cumulative damage even in early life or contribute little over the entire life

FIGURE 4

The stemness‐function model. This model posits the existence of two types of environment in an organism: the pro‐stemness state in the early life and regenerating cells, and probiological function in most tissues in the adult stage. Mild global activation of pro‐stemness genes in the pro‐function state may extend lifespan, whereas global overexpression of pro‐stemness genes may result in a detrimental effect

FIGURE 5

Two effects of in vivo reprogramming by Yamanaka (OSKM) factors are de‐differentiation and age reversal. De‐differentiation causes cells to go back to the stem cell lineage, whereas age reversal may lead to a younger biological age without de‐differentiation

FIGURE 6

Assessing the biological age of regenerated tissues. Tissues undergo spontaneous de‐differentiation and re‐differentiation during wound healing by regeneration. Many features are shared between this process and reprogramming. It is possible that the regenerated tissues are younger than the original tissues based on their biological age. An example of axolotl limb regeneration is shown