Abstract
Aging is a complex process characterized by the progressive alteration of cellular and tissue physiology. Modulated by genetic and epigenetic factors, it is accompanied by a modification of the cellular metabolism, a decrease in resistance to various cellular stresses and cellular senescence. The objective of this work is to use cell reprogramming as a strategy to delay the effects of aging by inducing global rejuvenation or by improving the regenerative capacities of the organism.The expression of four transcription factors: OCT4, SOX2, KLF4 and c-MYC (OSKM) allows the induction of somatic cell reprogramming into pluripotent cells. This so-called transient reprogramming, i.e., initiating the process without leading to the pluripotent state, has an immediate effect that partially erases the characteristic marks of tissue and cell aging. In order to determine how an early short transient cellular reprogramming affects aging processes in a whole animal, we induced OSKM expression in young progeric reprogrammable mice and revealed an increase in longevity at late ages and a protective effect on the integrity of tissue structures and on age-related pathologies, associated with modifications of epigenetic signatures in tissues. These results on late ages after an early transient reprogramming suggest a memory effect maintained throughout life. To explain these long-term effects, we explored the impact of an early transient reprogramming on metabolism. We were able to demonstrate a global modification of the body composition of the animals with a decrease of the fat mass gain in the young ages and a maintenance of this same fat mass in the late ages associated with a global modification of the ultrastructure and the metabolic activity of the white adipose tissue. This metabolic transition also seems to impact the muscle tissue with its own dynamics.The identification of the underlying mechanisms will allow us to define new strategies to prevent aging and senescence, which are at the origin of the appearance of age-related pathologies.