Early Life Reprogramming-Based Treatment Promotes Longevity

Abstract

Short-term expression of Yamanaka factors early in life promotes epigenetic reprogramming and an increased healthy lifespan in a mouse model of accelerated aging.

Aging is a universal feature of multicellular organisms and the primary risk factor for death from all age-related chronic diseases. Despite the apparent inevitable age-associated tissue deterioration, the aging process is surprisingly plastic. Manipulating genetic pathways (e.g., insulin-FoxO, TOR, AMPK, and sirtuin), as well as environmental intervention (e.g., dietary restriction and rapamycin treatment), can partially delay aging (Mahmoudi and Brunet, 2012). Most recently, partial reprogramming in vivo (i.e., the activation of the Yamanaka factors Oct4, Sox2, Klf4, and c-Myc [OSKM] in vivo) has been shown to erase age-associated defects—essentially reverting the biological clock (Ocampo et al, 2016).

Specifically, cyclic induction of the Yamanaka factors over the lifetime of an accelerated aging mouse model ameliorates aging-associated phenotypes and prolongs lifespan. Similar studies have demonstrated that partial reprogramming promotes rejuvenation of retinal ganglion cells, chondrocytes, dentate gyrus cells, and muscle progenitors, reinforcing the potential for reprogramming-based treatments in clinical settings (Mendelsohn et al, 2022). Of note, the rejuvenation of aging hallmarks by epigenetic remodeling induced by cellular reprogramming pinpoints the role of epigenetic alterations as a driver of aging.

Despite these early observations, important questions remain: (1) How does partial reprogramming in vivo revert the aging clock? (2) Could a transient reprogramming treatment early in life promote longevity? And finally, (3) Is age-related epigenetic drift efficiently erased by the Yamanaka factor expression across tissues? A study published last month reveals that a single short reprogramming-based treatment early in life in a progeria model extends lifespan, ameliorates aging phenotypes across tissues, and is sufficient to revert the epigenetic clock (Alle et al, 2022).

The first published reprogramming-induced rejuvenation protocol involves the induction of the Yamanaka factors for 2 days a week over the entire, but short lifetime of severely progeric mice (Lmna^G609G/G609G) (Ocampo et al, 2016). In an attempt to develop a protocol more suitable for clinical translation, Alle et al sought to explore the window of efficacy of OSKM, using a less severely progeric mouse (Lmna^G609G/+) as a model of accelerated aging. Surprisingly, inducing reprogramming for only 2.5 weeks at 2 months of age was sufficient to increase lifespan in progeric mice (Fig. 1). These data uncover for the first time the efficacy of a single-short reprogramming treatment in promoting longevity.

FIG. 1.

A single short reprogramming-based treatment early in life ameliorates tissue aging and improves fitness. Activation of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) in 2-month-old Lmna^G609G/+ mice—a HGPS mouse model—reverts aging features across tissue types and extends lifespan. This illustration has been partially created with BioRender. HGPS, Hutchinson–Gilford progeria syndrome.

The authors then explored the impact of early-life reprogramming on age-related pathologies in old mice. They found that elderly mice that had received reprogramming treatment when young exhibited improved motor skills and ameliorated age-related histopathological findings in the kidney, spleen, skin, and lung (Fig. 1). Collectively, these unexpected findings suggest that a single short pulse of OSKM early in life can initiate lifelong improvement of tissue integrity and motor skills maintained during aging.

Finally, Alle et al interrogated DNA methylation data to track the potential reversal of age-related epigenetic changes across tissues. DNA methylation on cytosine residues in mammals can be used as a clock to accurately measure chronological age (Stubbs et al, 2017). The authors reveal that OSKM expression at a young age rewires the DNA methylation landscape of different tissues, effectively delaying the epigenetic drift typically seen in old individuals.

Together, the study by Alle et al underscores the potential of reprogramming for organismal rejuvenation and regenerative medicine. A critical question that remains is how reprogramming factors permanently remodel the epigenetic landscape of diverse cell types in vivo, and further mechanistic studies are needed to explore how these promising findings could be translated into practice.

Authors' Contributions

Writing—reviewing and editing by B.D.S. and P.P.

Author Disclosure Statement

The authors declare they have no conflicting financial interests.

Funding Information

B.D.S. is a CPRIT Scholar in Cancer Research. Research in the Di Stefano Laboratory is supported by the Cancer Prevention & Research Institute of Texas Recruitment of First-Time, Tenure-Track Faculty Member Award RR200079, the American Society of Hematology Scholar Award, the Nancy Chang, PhD. Award for Research Excellence, and the NIH MIRA award 1R35GM147126-01.