Those who drink from the Fountain of Youth should take just a single sip. That would seem to be the lesson from a new study by Salk Institute researchers, who found that a brief burst of cellular reprogramming sufficed to reverse the hallmarks of aging in cultured cells, mice specially programmed to age rapidly, and wild-type mice.
Cellular reprogramming, accomplished via the expression of genes known as Yamanaka factors, is often used to induce pluripotency in cultured cells. While cellular reprogramming at the level of individual cells can turn the biological clock back to the embryonic stage, it hasn’t worked so well at the level of whole, living organisms.
Cellular reprogramming induces pluripotency, giving cells the ability to divide indefinitely and become any kind of cell type in the body. While rapid cell division is critical in growing embryos, in adults such growth is one of the hallmarks of cancer. Also, in adult animals, having large numbers of cells revert back to embryonic status in an adult could result in organ failure, ultimately leading to death.
For these reasons, the Salk team wondered whether they could avoid cancer and improve aging characteristics by inducing the Yamanaka factors for a short period of time. They decided to use genetic engineering to cause the intermittent expression of genes normally associated with the embryonic state. Ultimately, they found that when these genes were allowed a brief surge of expression, they were able to reverse the hallmarks of aging.
Details of this work appeared December 15 in the journal Cell, in an article entitled, “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.”
“[We] report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging,” wrote the article’s authors. “Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice.”
The authors described how their approach not only prompted human skin cells in a dish to look and behave young again, it also resulted in the rejuvenation of mice with a premature aging disease, countering signs of aging and increasing the animals’ lifespan by 30%. The authors asserted that this work provides insight both into the cellular drivers of aging and possible therapeutic approaches for improving human health and longevity.
“Our study shows that aging may not have to proceed in one single direction,” said Juan Carlos Izpisua Belmonte, the article’s senior author and a professor in Salk’s Gene Expression Laboratory. “It has plasticity and, with careful modulation, aging might be reversed.”
“Obviously, mice are not humans, and we know it will be much more complex to rejuvenate a person,” Izpisua Belmonte continued. “But this study shows that aging is a very dynamic and plastic process and therefore will be more amenable to therapeutic interventions than what we previously thought.”
Both mice and humans with progeria show many signs of aging, including DNA damage, organ dysfunction, and dramatically shortened lifespan. Moreover, the chemical marks on DNA responsible for the regulation of genes and protection of our genome, known as epigenetic marks, are prematurely dysregulated in progeria mice and humans. Importantly, epigenetic marks are modified during cellular reprogramming.
Using skin cells from mice with progeria, the team induced the Yamanaka factors for a short duration. When they examined the cells using standard laboratory methods, the cells showed reversal of multiple aging hallmarks without losing their skin-cell identity.
“In other studies, scientists have completely reprogrammed cells all the way back to a stem-cell-like state,” explained Pradeep Reddy, the article’s co-first author and a Salk research associate. “But we show, for the first time, that by expressing these factors for a short duration you can maintain the cell’s identity while reversing age-associated hallmarks.”
Encouraged by this result, the team used the same short reprogramming method during cyclic periods in live mice with progeria. The results were striking. Compared to untreated mice, the reprogrammed mice looked younger; their cardiovascular and other organ function improved and—most surprising of all—they lived 30% longer, yet did not develop cancer. On a cellular level, the animals showed the recovery of molecular aging hallmarks that are affected not only in progeria but also in normal aging.
Last, the Salk scientists turned their efforts to normal, aged mice. In these animals, the cyclic induction of the Yamanaka factors led to improvement in the regeneration capacity of pancreas and muscle. In this case, injured pancreas and muscle healed faster in aged mice that were reprogrammed, indicating a clear improvement in the quality of life by cellular reprogramming.
The Salk researchers believe that induction of epigenetic changes via chemicals or small molecules may be the most promising approach to achieve rejuvenation in humans. However, they caution that, due to the complexity of aging, these therapies may take up to 10 years to reach clinical trials.