Intermittent expression of genes normally associated with an embryonic state reverses aging in mammals and enables mice to live 30 percent longer

Scientists have shown it is possible to reverse ageing in animals. Scientists at the Salk Institute have found that intermittent expression of genes normally associated with an embryonic state can reverse the hallmarks of old age. Salk Institute researchers discovered that partial cellular reprogramming reversed cellular signs of aging such as accumulation of DNA damage. Progeria mouse fibroblast cells were rejuvenated by partial reprogramming.

Using a new technique allows mice to not only look younger, but live for 30 per cent longer. Human trials are projected within 10 years for a drug that would mimic the effects.

Scientists have known for some time that the four genes, which are known collectively as the Yamanaka factors, could turn adult cells back to their stem cell state, where they can grow into any part of the body.

But it was always feared that allowing that to happen could damage organs made from the cells, and even trigger cancer.

However, it was discovered that stimulating the genes intermittently reversed ageing, without causing any damaging side effects.

The technique involves stimulating four genes which are particularly active during development in the womb. It was also found to work to turn the clock back on human skin cells in the lab, making them look and behave younger.

The early-stage 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,” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory and senior author of the paper appearing in the December 15, 2016, issue of Cell. “It has plasticity and, with careful modulation, aging might be reversed.”

As people in modern societies live longer, their risk of developing age-related diseases goes up. In fact, data shows that the biggest risk factor for heart disease, cancer and neurodegenerative disorders is simply age. One clue to halting or reversing aging lies in the study of cellular reprogramming, a process in which the expression of four genes known as the Yamanaka factors allows scientists to convert any cell into induced pluripotent stem cells (iPSCs). Like embryonic stem calls, iPSCs are capable of dividing indefinitely and becoming any cell type present in our body.

Induction of reprogramming improved muscle regeneration in aged mice. (Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. Credit Salk Institute

Journal Cell – In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

Highlights

•Partial reprogramming erases cellular markers of aging in mouse and human cells
•Induction of OSKM in progeria mice ameliorates signs of aging and extends lifespan
•In vivo reprogramming improves regeneration in 12-month-old wild-type mice

Summary

Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, 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. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.

“What we and other stem-cell labs have observed is that when you induce cellular reprogramming, cells look younger,” says Alejandro Ocampo, a research associate and first author of the paper. “The next question was whether we could induce this rejuvenation process in a live animal.”

While cellular rejuvenation certainly sounds desirable, a process that works for laboratory cells is not necessarily a good idea for an entire organism. For one thing, although rapid cell division is critical in growing embryos, in adults such growth is one of the hallmarks of cancer. For another, 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.

To find out, the team turned to a rare genetic disease called progeria. 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.

sing 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,” says co-first author Pradeep Reddy, also 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 percent 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.

“This work shows that epigenetic changes are at least partially driving aging,” says co-first author Paloma Martinez-Redondo, another Salk research associate. “It gives us exciting insights into which pathways could be targeted to delay cellular aging.”

Lastly, 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.

“Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person,” says Izpisua Belmonte. “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.”

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.

Introduction

Embryonic development occurs as a unidirectional progression from a single-cell zygote to an adult organism. During embryogenesis and early stages of life, cells undergo a spatiotemporally orchestrated differentiation process, leading to the generation of all of the cell types that comprise an adult organism. These events take place within a stable environment that minimizes molecular and cellular damage. As an organism ages, however, there is a continuous and progressive decline in the mechanisms responsible for minimizing cellular damage. This eventually results in an organism’s inability to maintain homeostasis

The last decade of scientific research has dramatically improved our understanding of the aging process. The notion that cells undergo a unidirectional differentiation process during development was proved wrong by the experimental demonstration that a terminally differentiated cell can be reprogrammed into a pluripotent embryonic-like state. Cellular reprogramming to pluripotency by forced expression of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc [OSKM]) occurs through the global remodeling of epigenetic marks. Importantly, many of the epigenetic marks that are remodeled during reprogramming (e.g., DNA methylation, post-translational modification of histones, and chromatin remodeling) are dysregulated during aging. In fact, epigenetic dysregulation has emerged as a key hallmark of the aging process. Several groups, including ours, have observed an amelioration of age-associated cellular phenotypes during in vitro cellular reprogramming. Reprogramming of cells from centenarians or patients with Hutchinson-Gilford progeria syndrome, (HGPS) a disorder characterized by premature aging, resets telomere size, gene expression profiles, and levels of oxidative stress, resulting in the generation of rejuvenated cells.

SOURCES- Cell, Salk Institute, Telegraph UK, Youtube

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