Emerging rejuvenation strategies-Reducing the biological age

Abstract

Several interventions have recently emerged that were proposed to reverse rather than just attenuate aging, but the criteria for what it takes to achieve rejuvenation remain controversial. Distinguishing potential rejuvenation therapies from other longevity interventions, such as those that slow down aging, is challenging, and these anti-aging strategies are often referred to interchangeably. We suggest that the prerequisite for a rejuvenation intervention is a robust, sustained, and systemic reduction in biological age, which can be assessed by biomarkers of aging, such as epigenetic clocks. We discuss known and putative rejuvenation interventions and comparatively analyze them to explore underlying mechanisms.

Keywords: aging; biomarkers; epigenetic clocks; rejuvenation.

FIGURE 1

Timeline of advances in rejuvenation research. Several potential rejuvenation therapies that fall into the three major categories are listed in chronological order. Treatments marked in red show a reversal in biological age as assessed by epigenetic clocks. Additional studies not shown on this timeline are described in Table 1. RF, reprogramming factor

FIGURE 2

Heterochronic transplantation in mouse models. Schematic of potential heterochronic transplantation interventions for rejuvenation in mice

FIGURE 3

Reprogramming approaches for rejuvenation. Schematic of reprogramming approaches for rejuvenation in vitro and in vivo. Full reprogramming of cells in vitro can reverse biological age to that of the embryo, but this approach can be tumorigenic in vivo. Partial reprogramming could reverse biological age of the cell without an irreversible change of cell identity, and the in vivo approach may be promising in order to achieve rejuvenation

FIGURE 4

Damage dilution in rejuvenation. Schematic of damage dilution, a potential mechanism shared between embryonic rejuvenation and heterochronic transplantation. In (a), heterochronic transplantation, the damage accumulated with age is likely diluted by donor tissues (i.e., young blood), resulting in lower DNAm age readouts. In early embryonic development (b), this is done through cell division, unequal distribution of damage, and an increase in cellular maintenance and repair machinery. In a single cell, damage can only be cleared at a certain rate, depending on the abundance of maintenance mechanisms (top). During highly proliferative states (bottom), damage is distributed (likely unequally) to different cells, which can each handle the reduced damage with their own repair tools. Bulk and single‐cell clocks may be used to assess biological age readouts resulting from these phenomena

FIGURE 5

Relationships between different rejuvenation paradigms. Schematic of the connections between three putative rejuvenation strategies. Embryonic rejuvenation and heterochronic transplantation share a common potential mechanism (damage dilution), and embryonic rejuvenation and reprogramming factor expression both involve common changes in gene expression. Additionally, heterochronic transplantation and reprogramming both result in a significant elevation of regenerative capacity. Harnessing the connections between current and future rejuvenation therapies may lead to a more comprehensive framework of rejuvenation, which could enable its eventual systemic application in humans