Regenerative Medicine and the Biology of Aging

Evolving concepts in the biology of aging are beginning to articulate mechanistic understanding of important signaling targets operative in the process of aging, paving the way for meaningful therapeutic intervention (1,2). These concepts dovetail importantly with the science of regenerative medicine, which may offer potential interventions. This issue of the Journal of Gerontology contains a special collection of papers devoted to regenerative medicine focused on the potential of adult stem cells. Several important themes emerge from this compendium that is helpful in guiding the field forward. First, there is growing recognition that cell-based therapy may play a role in offsetting age-related disease (1–3). Second, as with other fields, there is the recognition that miRNAs may transduce key bioactivity and participate as modulators of antiaging pathways (4,5). Third, genetics plays an important role by providing a predisposition to healthy aging (6), and finally other important signaling pathways may be implicated, which in turn may serve as therapeutic targets (7).

Cell-Based Therapy for Aging-Related Conditions

With regard to cell-based therapy, Wang and colleagues performed an exciting study in a rat model of vascular dementia, in which they show synergistic effects of combining mesenchymal stem cell (MSC) transplantation and transcranial magnetic stimulation, leading to improved cognition in a rat model of vascular dementia (8). These findings have therapeutic implications for a number of neuro-cognitive disorders, and the findings are highly relevant given that MSCs are in clinical trials for a large number of neurological and aging-related conditions (1–3). In another paper, Ledesma-Martinez et al. reviewed the role of MSCs for regeneration of periodontal tissue in elderly individuals (9). These authors discuss the important concept of the use of allogeneic MSCs in order to circumvent the issue of aging-induced impairment of autologous cell sources, and propose cell intrinsic mechanisms of exogenous MSCs could overcome age-associated alterations of the niche; in this case, the periodontial tissue. They also highlight limitations of the clinical translatability of the current literature given the heterogeneity of the cells reported as MSCs. As before, this is a relevant topic given the growing acceptance of allogeneic strategies that are emerging in clinical trials (10,11)

The Role Played by miRNAs in the Modulation of Antiaging Pathways

It is increasingly appreciated that cell-based therapeutics may transduce therapeutic bioactivity through the release of exosomes and other extracellular vesicles, structures, which contain many miRNAs and other noncoding RNAs (12). Bae et al. performed microarray analysis of extracellular microRNAs released from embryonic stem cells and identified, using bioinformatic approaches, candidate microRNAs with antisenescent activity. With this approach, they identified mmu-miR-291a-3p, which had antisenescent activity on cultured dermal fibroblasts largely mediated through the TGF-β receptor 2 (13). Similar to the improving wound healing seen after removal of senescent cells (14), the authors show enhanced wound healing in aged mice after exposure in vivo to the Embryonic stem cell-derived exosomes (ESC-derived exosomes). Highlighting potential negative roles miRNAs can play in aging phenotypes, Periyasamy–Thandavan performed an analysis of microRNAs involved in SDF-1 signaling from bone marrow–derived stromal cells. MicroRNA-141-3p diminished SDF-1 gene expression. Because miRNA-141-3p increases with age, the reduction in SDF-1 could represent an age-related pathway, which in turn could reduce osteogenesis given the role that SDF-1 plays in osteogenic differentiation (15). These findings of negative regulation of SDF-1 by a microRNA may also have important implications in loss of other adult stem cell compartments, especially hematopoietic stem cells, as SDF-1 acts as a critical niche regulator.

In another study examining secreted products that could influence the aging process, Al-Dabbagh et al. examined the secretomes of young versus old lymphocytes on C2C12 myoblast regeneration. Conditioned media from older, activated T-lymphocytes has decreased levels of amphiregulin and IGF-1 when compared with younger cells. Treatment with conditioned media produced differential effects on a number of important kinases (16). Thus, aging lymphocytes may contribute to differential regenerative responses of C2C12 myoblasts in this in vitro model.

Collectively, these studies highlight differential paracrine effects related to aging and highlight the role that miRNAs play in transducing this bioactivity. All three studies provide insights into using miRNAs and other secreted products to potentially offset biological pathways contributing to aging.

Genetics

Variations in longevity prompt the important questions of underlying genetic predisposition to longevity. Nygaard and colleagues performed whole-exome sequencing in a cohort of individual aged 98–108 years of age in search of genetic contributions to their longevity. While they were unable to detect a unique protein-altering variant or individual gene association, they did detect three genes of nominal significance that were associated with older age; these genes included LYST, MDN1, and RBMXL1. In their analysis, they were also able to identify other genes that conferred increased risk for Alzheimer’s disease (17). These early stage analyses certainly prompt larger genetic analyses among centenarian populations.

In another genetic study, Ingles et al. examined pluripotency gene expression in periperhal blood mononuclear cells of centenarians versus octogenarians. In this polymerase chain reaction–based study, the level of these genes (Yamanaka factors) was decreased in octogenarians relative to young healthy control, and restored towards normal in the centenarian population (18). They further demonstrate upregulation of the expression of pluripotent genes in octogenarian blood cells after transduction with Bcl-xL, a gene which is already highly expressed in centenarian cells. This potentially important observation offers insights into factors expressed in lymphocytes that may contribute to successful aging.

Klotho Deficiency and Telomerase Activity

Ullah and Sun knocked down the antiaging protein Klotho in adipose-derived stem cells and showed that decreasing Klotho led to diminished telomerase activity through changes in TERF1 and TERT. This could be offset using cycloastragenol, which partially rescued the decline in telomerase (19). Thus, modulation of Klotho may serve as a means to alter telomerase activity.

In summary, insights into the biology of mammalian aging are progressing and we are beginning to explore the potentials for coupling the emerging field of regenerative medicine with concepts of therapeutic interventions. The compendium of articles published here highlights some of the key themes that bring together cell-based therapy, miRNA biology, signaling, and genetics, all with a focus on aging. These studies highlight current state-of-the-art technologies and help pave the way for future important studies that have potential translational and therapeutic impact.

Funding

Joshua M. Hare is funded by following grants: UM1 HL113460, R01 HL134558, R01 HL107110, and Soffer Family Foundation.

Conflict of Interest

J.M.H. reported having a patent for cardiac cell-based therapy. He holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. J.M.H. is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron and holds equity in Longeveron. He is also the coinventor of intellectual property licensed to Longeveron. Longeveron and Vestion did not contribute funding to this work.