Reprogramming: Emerging Strategies to Rejuvenate Aging Cells and Tissues

Abstract

Aging is associated with a progressive and functional decline of all tissues and a striking increase in many "age-related diseases". Although aging has long been considered an inevitable process, strategies to delay and potentially even reverse the aging process have recently been developed. Here, we review emerging rejuvenation strategies that are based on reprogramming toward pluripotency. Some of these approaches may eventually lead to medical applications to improve healthspan and longevity.

Keywords: aging; epigenetics; iPSC; reprogramming; senescence; stem cells.

Figure 1

Hallmarks of aging at the origin of age-related diseases. Aging is characterized by a progressive loss of biological functions linked to the appearance and accumulation of molecular and cellular damage over entire lives. This damage has been classified into three categories by López-Otín [1]. (i) Primary hallmarks corresponding to molecular disorders occurring in cells: genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. (ii) Antagonistic hallmarks, corresponding to alterations of damage response mechanisms: deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. Finally, (iii) integrative hallmarks corresponding to tissue homeostasis failures: stem cell exhaustion and altered intercellular communication. Altogether, these interconnected hallmarks of aging act as cause and catalyst engendering a large set of age-related pathologies affecting the whole body.

Figure 2

Applications of cell reprogramming and hPSCs to restore altered or aged tissues. Due to increased life expectancy and global population aging, two major health issues are arising: increased prevalence of age-associated pathologies whose mechanisms remain only partially explored and understood, and increased age-associated tissue deterioration and loss of function. Therefore, human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs), nuclear transfer stem cells (ntSCs) and induced pluripotent stem cells (iPSCs) emerged as tools to model both age-associated pathologies and tissue deterioration: from 2D cell culture to 3D complex reconstructed tissues, through organoids, and cells or tissue replacement strategies. Thanks to cell reprogramming [4,71], iPSCs made it possible to envisage autografts, especially in aged patients, as reprogramming erases aging marks in iPSCs and allows production of “rejuvenated” cells after differentiation [128].

Figure 3

Partial reprogramming toward pluripotency as a new anti-aging strategy. For decades, complete cell reprogramming has been demonstrated to reset somatic cell physiology to a juvenile state equivalent to ESCs. Starting from transgenic models allowing inducible reprogramming factor expression to non-integrative vectors; numerous studies have recently demonstrated that a partial reprogramming is sufficient to restore the general characteristics of cellular aging without changing the identity of the cells. These innovative approaches pave the way for new strategies based on a safe transient reprogramming that can be directly transposed to humans.