Partial cellular reprogramming by expression of reprogramming factors can restore youthful epigenetic signatures to aging cells and delay aging phenotypes.

Aging is a complex and inevitable process that affects all organisms – and it is associated with tissue dysfunction, susceptibility to various diseases, and death [1]. The development of strategies like cellular reprogramming for increasing the duration of healthy life and promoting healthy aging is difficult since the mechanism of aging is not understood clearly. Aging is known to be associated with several hallmarks of aging – such as epigenetic alterations, genomic instability, cellular senescence, telomere shortening, mitochondrial dysfunction and altered intercellular communication.

Aging can be divided into two major phases: healthy aging and pathological aging. Healthy aging is the phase where the accumulation of minor alterations takes place, but pathological aging is the phase where clinical diseases and disabilities predominate along with the impairment of physiological functions [2].

Longevity.Technology: Notions regarding cells undergoing a unidirectional differentiation process during development existed previously [3]. However, in recent years cellular reprogramming using transcription factors has emerged as an important strategy for the rejuvenation of aging cells, erasing markers of cell damage and restoring epigenetic markers. These transcription factors also known as Yamanaka factors include Oct4, Sox2, Klf4, and c-Myc (OSKM). They can convert terminally differentiated somatic cells into pluripotent stem cells which are capable of dividing into any cell type of the body and thus can improve the health and longevity of individuals.

Most of the previous studies on cellular reprogramming were performed in a mutant background that displayed an accelerated aging syndrome, which could lead to a possibility of mutation in the OSKM-elicited phenotypes. However, to address such concerns and evaluate the feasibility of age reversal by partial OSKM reprogramming, a new study has evaluated the impact of partial cellular reprogramming in physiologically aging wild-type (WT) mice.

The study involved the administration of doxycycline (a broad-spectrum antibiotic used in the treatment of bacterial infections) in drinking water for 2 days, followed by 5 days of withdrawal to analyse the systemic expression of OSKM. The mice were divided into three different cohorts: for one the cellular reprogramming treatment started at 15 months of age and continued until 22 months of age; for another the treatment was started at 12 months of age and continued until 22 months of age; and for the third cohort the treatment started at 25 months of age and continued for 1 month. The first two were defined as long-term regimens while the last one was defined as a short-term treatment [4].

The results of the study reported that a significant reduction of epigenetic age is observed in the kidney and skin in the case of long-term partially cellular reprogrammed animals. This change is reflected in transcriptomic signatures leading to a reduction in senescence, inflammation signatures, and stress response pathways. Also, the skin of female mice was found to respond more effectively to cellular programming as compared with male mice.

The study also showed that long-term cellular reprogramming improved wound healing and reduced the accumulation of fibrotic tissue in the wound area. However, short-term reprogramming resulted in minor epigenetic changes and different transcriptomic changes when compared with long-term treatment.

Furthermore, long-term partial cellular reprogramming was found to be safe and not associated with any negative consequences such as the formation of teratoma. The authors conclude that long-term partial reprogramming can be used as an effective intervention for not only the reversal of age but also for the prevention of age-associated diseases, thereby improving longevity and promoting healthy life [4].

“The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways,” say the authors Browder, Reddy, Belmonte et al.

“Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes. We further conclude that longer-term partial reprogramming regimens are more effective in delaying aging phenotypes than short-term reprogramming [4].”

[1] https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01158-7
[2] https://www.mdpi.com/1422-0067/22/8/3990
[3] https://www.cell.com/fulltext/S0092-8674%2816%2931664-6
[4] https://www.nature.com/articles/s43587-022-00183-2