Systems biology of the individual stochastic timer of aging

ongoing

Aging is the biggest risk factor for frailty and death. However, we lack basic understanding of a fundamental question: Why do genetically identical organisms raised in the same conditions get sick and die at different times? If we understood the stochastic timer that drives aging in each individual, we could devise ways to turn back the timer and treat age-related diseases, extending the healthy lifespan. This requires addressing both molecular and social factors that vary between individuals, such as socioeconomic status in humans and social ranking in mice, which impact every aspect of aging. This synergy program aims to identify the stochastic timer of aging and develop methods to read the timer and turn it back. We use mice as a tractable organism relevant to human aging, and combine three disciplines: 1) systems biology to mathematically define the stochastic timer of aging and the basic concepts needed to understand its production, removal and noise processes; 2) neurobiology of behavioral individuality; and 3) biology of cellular senescence, which studies the most promising candidate for the timer: senescent cells that accumulate with age, causing chronic inflammation and whose removal delays age-related decline. To pinpoint the timer, we will follow the natural variability of large cohorts of genetically identical mice, tracked across the lifespan by video and RFID tags. We will measure a battery of behavioral, physiological and molecular parameters, as well as senescent cells in multiple organs throughout life. We will use new mouse models that allow us to visualize, pull down and ablate senescent cells, to provide full molecular profiles of senescent cells in different organs and to characterize their immune-surveillance mechanisms. This study will provide basic understanding of the timer of aging and provide ways to read the timer. Moreover, we will offer new ways to set back the timer in order to address age-related diseases and functional decline.