Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.

The technology of reprogramming differentiated cells into a pluripotent state, which can be used to derive virtually any cell type in vitro, has ignited the field of regenerative medicine. "n equally revolutionary, but yet to be harnessed phenomenon, is the reset of age that occurs en route to pluripotency. This rejuvenation is clearly evident during reproduction, resulting in a young offspring from aged parental cells. "rtificial reprogramming techniques built off this process, such as somatic cell nuclear transfer SCNT and induced pluripotent stem cell iPSC reprogramming techniques, are showing growing evidence for rejuvenation at the cellular level. These findings all points to an intimate relationship between reprogramming to pluripotency and the reset of age, and iPSC technology, especially, offers the possibility of a man-made intervention in the aging process. Though in vitro cell reprogramming has been studied arguably for the last three decades, this application of specifically developing a protocol to rejuvenate cells, tissues, even whole organs has only just begun to be explored. There are still many challenges to realization but this technology has already famously shown that cell differentiation is more than a one-way street, and, maybe, so is aging.

Modeling the dynamics of aging often involves attempting to identify a handful of causal factors and correlating it to some ordered and/or disordered evolution. However, this approach may completely overlook the reality of aging as a distributed and complex evolution. Additionally, the theory driving aging should not just be about the how, but also the why, in that there should be motivated objectives and principles behind growth, decay and alternative routes like reproduction. All of these features are incorporated into a new, theoretical model for the aging process proposed herein. It incorporates a number of techniques from other fields that regularly characterize and predict complex systems dynamics.

Skin is the largest human organ system, and its protective function is critical to survival. The epithelial, dermal, and subcutaneous compartments are heterogeneous mixtures of cell types, yet they all display age-related skin dysfunction through the accumulation of an altered phenotypic cellular state called senescence. Cellular senescence is triggered by complex and dynamic genetic and epigenetic processes. A senescence steady state is achieved in different cell types under various and overlapping conditions of chronological age, toxic injury, oxidative stress, replicative exhaustion, DNA damage, metabolic dysfunction, and chromosomal structural changes. These inputs lead to outputs of cell-cycle withdrawal and the appearance of a senescence-associated secretory phenotype, both of which accumulate as tissue pathology observed clinically in aged skin. This review details the influence of genetic and epigenetic factors that converge on normal cutaneous cellular processes to create the senescent state, thereby dictating the response of the skin to the forces of both intrinsic and extrinsic aging. From this work, it is clear that no single biomarker or process leads to senescence, but that it is a convergence of factors resulting in an overt aging phenotype.