Abstract
Aging is a complex process modulated by genetic and epigenetic factors and marked by progressive appearance of age-related pathologies and decrease of cell and tissue regenerative capacity. Our objective is to delay these effects by inducing global rejuvenation or increasing the organismal regenerative capacity.In 2007, Dr. Yamanaka showed that human fibroblasts can be converted into pluripotent stem cells by inducing the expression of four transcription factors. Ourselves, we showed in 2011 that senescent cells which are accumulating in aging organisms can be reprogrammed and regained a rejuvenated physiology and metabolism.Our hypothesis is that in vivo induction of a transient reprogramming process could erase the marks of cellular aging and improve tissue regeneration to restore altered cell physiology and delay tissue aging and deleterious consequences.For this, we used a transgenic mouse model to control the induction of the expression of the reprogramming factors in order to reprogram the cells of the whole organism. These mice also recapitulate the human phenotype of Hutchinson-Gilford progeria syndrome, mimicking accelerated physiological aging.Our results showed a significant increase in life expectancy and improvement in tissue integrity related to activation of tissue regeneration. The impact of controlled transient reprogramming on age-related pathologies has also been monitored and a protective role in osteoarthritis and osteoporosis has been observed in these animals at eight months of age. Also, a two-week low-dose treatment, at two months of age, allows for increased life expectancy in later ages while decreasing phenotypic markers associated with aging suggesting a memory effect of transient reprogramming maintained along the entire life.This work demonstrates how transient cellular reprogramming reduces the negative impacts of aging at the organismal level.