From aging clocks to molecular mechanisms: novel strategies to combat aging

Age-related diseases, such as cancers, type 2 diabetes, cardiovascular, and neurodegenerative disorders, are the main causes of disability and death in humans. The aging process is a major causal factor in the development of age-related diseases and is characterized by the progressive accumulation of damage at molecular, cellular, tissue, and organismal levels. Therefore, targeting aging is a promising strategy for improving human health and extending life. My thesis focuses on identifying and characterizing novel interventions to slow aging and reverse its consequences using cutting-edge experimental and computational approaches.A central challenge in targeting aging lies in how to measure aging progression in the form of biological age. Although machine learning models trained on molecular data can accurately estimate biological age, a systematic framework for discovering age-modifying interventions at scale has been lacking. To address this, we developed ClockBase, a comprehensive platform and database encompassing ~2 million human and mouse DNA methylation and RNA sequencing samples with corresponding biological age estimates. ClockBase employs an autonomous artificial intelligence (AI) agent to perform large-scale, unbiased analyses across multiple aging clock models, enabling the identification of interventions that modulate biological age. Among these, we validated ouabain as a potent candidate geroprotector, with its systemic aging-mitigating effects largely mediated by upregulation of the neuronal regeneration related protein (Nrep) gene. Ouabain preserved health by attenuating frailty progression, reducing neuroinflammation, and improving cardiac function in mice. While slowing aging can delay the onset of age-related diseases and functional decline, rejuvenation offers the potential to not only treat existing conditions but also to prevent their future emergence. Exposure of aged organisms to a young systemic environment has been shown to induce widespread rejuvenation, yet the extent to which individual organs can be intrinsically rejuvenated and the underlying mechanisms driving such effects remain largely undefined. Subcutaneous white adipose tissue (WAT) is heavily understudied in the context of aging despite its crucial role in maintaining immune, endocrine, and energy homeostasis. Therefore, studying the possibility and mechanisms of its rejuvenation may be critical to combat aging. To evaluate whether adipose tissue can undergo rejuvenation or accelerated aging depending on host environment, we transplanted subcutaneous WAT from young and old donor mice into young and old recipients and tracked biological age dynamics longitudinally in the grafted fat. Using epigenetic, transcriptomic, and histological biomarkers of aging, we demonstrate that the systemic environment of the host has a profound influence on the biological age of transplanted adipose tissue. Most importantly, we show that old WAT can be rejuvenated in a young body. Specifically, both epigenetic and transcriptomic aging clocks revealed a reduction in biological age, driven by the upregulation of canonical and previously unrecognized genes involved in thermoregulatory remodeling of WAT. Rejuvenation was further supported by a shift in tissue architecture toward a more youthful state, marked by reductions in adipocyte lipid droplet size and decreased heterogeneity within the adipocyte population.In summary, my work establishes a novel framework for unbiased discoveries of aging-modifying interventions and introduces a foundational model for understanding the mechanisms of rejuvenation. Together, my research will advance the development of strategies to improve human health and extend life.