Emerging strategies for biological age reversal

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, as these anti-aging strategies are often referred to interchangeably. My studies suggest that the prerequisite for a rejuvenation intervention is a robust, sustained and systemic reduction of biological age, which can be assessed by biomarkers of aging, such as epigenetic clocks. In this thesis, I examine two putative rejuvenation interventions and discuss tools to analyze it. Chapter 1 offers an overview of approaches that have the potential to reverse the biological age of mammals. These approaches can be separated into several groups. I discuss general principles of aging and rejuvenation, interventions for both and methods that may be used to assess these transitions. As an example, precise biomarkers of aging based on omics approaches can be important tools in the analyses of these potential interventions. In this chapter, I discuss specific rejuvenation strategies that are validated or remain to be unexplored, as well as specific biomarkers that could assess their effects. Chapter 2 describes a novel tool to analyze the biological age, which is a biomarker of aging based on trace elements. This tool is based on changes in tissue element composition (ionome) and analyses of control and calorie restricted mice. To carry out this study, I quantified changes in the ionome across 8 organs and 16 age groups of mice. The dataset prepared allowed to uncover various features of trace elements and develop organ-specific ionomic biomarkers that could track the aging process and report the longevity effect of caloric restriction. This biomarker has the potential to become an accessible tool to complement other aging clocks in examining progression through aging in various tissues and biological age-modulating effects of interventions. Chapter 3 describes a quantitative biological age analysis of a well-known procedure called heterochronic parabiosis. This experiment is performed by joining the circulation system of two mice of different ages. By applying the DNA methylome-based aging biomarker called the epigenetic clock, I examined the biological age of mice undergoing parabiosis and found that a 3 month treatment extends the lifespan of old mice and reduces their biological age in both blood and liver. Chapter 4 discusses the model of bone marrow transplantation. As we discovered that heterochronic parabiosis greatly reduced the biological age of old animals, I carried out a heterochronic bone marrow transplantation experiment with a 6-month follow up to examine if blood cells can recapitulate the effect of heterochronic parabiosis, and to explore biological age dynamics of the host and transplanted tissues. I observed that the biological age and age-associated phenotypes of blood cells was greatly influenced by the age of the recipient. I further found that frailty index, liver epigenetic age and mortality of old animals was not affected by the transplanted young bone marrow during the follow up period. In contrast, the epigenetic age of the liver of the young recipients was slightly increased by the aged bone marrow.