Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Abstract

The expression of the pluripotency factors OCT4, SOX2, KLF4 and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, cycles of brief OSKM expression do not change cell identity but can reverse markers of aging in cells and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic and metabolomic changes towards a younger configuration in multiple tissues and in the serum.

Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver

“…The importance of epigenetic and transcriptional alterations in the aging process is underscored by several recent studies that employed partial reprogramming—an inherently epigenetic phenomenon—to rejuvenate several tissues in a variety of different aging models. Such rejuvenation phenomena do not only positively impact physiology, but also established a more youthful epigenetic state as measured by changes in the DNA methylation pattern (Lu et al , 2020 ; preprint: Chondronasiou et al , 2022 ), the levels of histone modifications (Ocampo et al , 2016 ), and the transcriptome itself (Lu et al , 2020 ). In summary, epigenetic and transcriptional states change with age and are directly linked to physiological fitness.…”

Aging and cancer epigenetics: Where do the paths fork?

“…Furthermore, if we acknowledge that tumoral cells-and not exclusively cancer stem cells-have an increased quality of stemness, or plasticity, which increases their proliferation and dissemination potential (Batlle & Clevers, 2017), should we expect them to have a higher or lower epigenetic age? There is evidence that some stem-related traits such as telomerase expression do not lead to the rejuvenation of the epigenetic clock (Lu et al, 2018), while, as mentioned previously, the induction of pluripotent reprogramming factors does (Chondronasiou et al, 2022;Gill et al, 2022;Sarkar et al, 2020).…”

“…Indeed, the intrinsic characteristics of DNAm clocks in relation to their differing "ticking rates" during lifespan, which are accelerated during development and subsequently slow down during aging, (Horvath & Raj, 2018) suggest that they may be particularly linked to an underlying biological system. Stem cells display a youthful-pre-natal in fact-epigenetic phenotype (Horvath, 2013) and there are experimental observations indicating that the rejuvenation of the epigenetic clock occurs during embryonic development (Kerepesi et al, 2021) and can be achieved through the transient expression of reprogramming factors in human and mouse models (Chondronasiou et al, 2022;Gill et al, 2022;Sarkar et al, 2020). Thus, the ticking rate of the epigenetic clocks could in fact reflect those developmental and tissue-homeostasis maintenance processes driven by stem cells-and involving alterations in cell composition-that occur throughout life, processes, which can in turn be modified by internal or external factors during aging (Horvath & Raj, 2018;Raj & Horvath, 2020).…”

In vivo reprogramming leads to premature death due to hepatic and intestinal failure

“…Therefore, in order to avoid the adverse effects and early lethality associated with in vivo reprogramming, most studies have typically focused on the short-term expression of the reprogramming factors at organismal level, or more recently, the tissue-or organ-specific expression. In this line, to induce whole body expression of OSKM in the absence of side effects, researchers have commonly used short-term cyclic expression of the OSKM factors, such as 2 days (Browder et al, 2022;Ocampo et al, 2016) or 3 days (Rodriguez-Matellan et al, 2020) of doxycycline (1mg/ml) followed by 5 or 4 days withdrawal, or lower concentration of doxycycline (0.2 mg/ul) for 7 days (Chondronasiou et al, 2022).…”

“…Furthermore, reprogramming of aged mice has the capacity to improve memory (Rodriguez-Matellan et al, 2020), regenerate skeletal muscle and pancreas following injury (Chiche et al, 2017;Ocampo et al, 2016), restore vision loss in injured retina (Lu et al, 2020), and recently, rejuvenate multiple tissues and organs (Browder et al, 2022;Chondronasiou et al, 2022). Finally, cyclic induction of reprogramming has been shown to extend lifespan in a progeria mouse model (Alle et al, 2021;Ocampo et al, 2016).…”