Thinking of biological aging as analogous to a clock, research has given us two distinct avenues of lifespan-extending intervention: the clock can be either slowed down or wound back. Most research has with dealt the former, but the latter is very promising—especially for those whose clock has been winding for some time. Commonly referred to as rejuvenation therapies, these approaches typically utilize stem cells.

From a developmental perspective, stem cells can be considered neophytes of the cellular world. They are not specialized cells like liver cells, skin cells, or any variety of mature cells that provide a specific physiological utility, but foundational cells having “instructions” and capable of transforming into a variety of specialized cell types. Stem cells have the capacity to replace nearly any cell type in the body, a characteristic known as pluripotency. It has, however, been a challenge to make use of these cells as they must be harvested and then grown under very specific conditions to produce amounts sufficient for therapeutic administration without disrupting their characteristic versatility.

In 2007, Nobel Prize-winning biologist Shinya Yamanaka pioneered research devising a means with which to reprogram mature, differentiated cells back to stem cells. Forced expression of four proteins, known as Yamanaka factors, is capable of inducing a sort of “cellular amnesia”, resulting in a reversion to their original and more versatile or pluripotent state. This innovation alleviated some of the more technically challenging aspects of growing stem cells. Application of the Yamanaka factors in cell culture and advanced aging animal models results in a delayed aging phenotype; however, in animal models, long-term continuous exposure to these factors has been shown to induce cancer, specifically teratomas, resulting in premature death.

Nature Aging has published a study detailing an approach to long-term activation of these factors that might delay aging while avoiding the risk of developing cancer. The key to this novel approach is periodic expression. The study authors generated a mutant mouse in which the expression of Yamanaka factors could be controlled through the administration of the antibiotic doxycycline. This allowed for mice to be treated for 2 out of 7 days per week.

Gene expression can be regulated in a variety of ways, one of which is through modifications to the chromatin structures that DNA is spooled around—a process known as methylation. These methylated sites are collectively referred to as epigenetic marks, and they add a layer of control to gene expression. The pattern of epigenetic marks is highly correlated with biological aging, and as a result this pattern, also known as the epigenetic clock, can be used to determine the efficacy of an intervention’s ability to modulate rates of aging.

The epigenetic clock in old animals exposed to long-term, periodic expression of the Yamanaka factors was similar to those of young animals in both skin and kidney tissue and in gene expression patterns; specifically, reductions were shown to genes related to senescence and inflammation, two factors thought to be significant drivers of aging. This suggests that the treatment was effective in maintaining or possibly rejuvenating these particular tissues. Additionally, with regard to skin, treated animals showed improvements in their capacity to recover from injury as assessed by wound healing experiments, further suggesting maintenance of a youthful state. Although this method of treatment was able to exert a change in both the skin and kidneys, it did not significantly change the epigenetic status of the liver, spleen, lung, or muscle tissues.

Further analysis of metabolites was performed to assess changes beyond gene expression. In this regard, older animals treated for an extended period had similar metabolite profiles to that of younger animals, indicating that this treatment may be restoring or preserving a more youthful metabolic state. These metabolic changes were seen in a variety of tissues beyond the skin and kidneys, suggesting that periodic long-term exposure to Yamanaka factors might be facilitating a more youthful phenotype in a systemic manner without affecting the epigenetic status of all tissues.

In contrast to the prolonged treatment starting in mid-life, the authors also examined a short-term exposure in older animals. The approach resulted in gene expression reductions in stress pathways, but the majority of analysis was inconsistent with the beneficial changes produced by long-term treatments. Although the short-term application of this therapy did not recapitulate the effects of long-term interventions, there may be an earlier, yet still advanced age and period by which this approach can provide a benefit.

Importantly, this research has demonstrated that the Yamanaka factors can be applied in a seemingly safe manner through a periodically controlled method, and that it may be possible to fine tune this method to maximize its benefits.

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