By Rita Beamish

If the body’s old cells can be made to act young again, are they really regaining their youth, or is it just a superficial manifestation of their younger selves?

The answer to this question – which has vast implications for regenerating the body’s functionality and vitality in the face of injury and disease – depends on elusive portraits of what exactly are the characteristics of cells as they age. It’s not just how they function but how their intrinsic structural features may change that determines whether they are really youthful, and thus able to divide and reproduce with the vigor of youth.

Making strides toward solving the puzzle is Dr. Thomas Rando, a Stanford neurology professor and researcher whose team recently discovered differences in the chemical markings on the protein husks that surround a cell’s DNA.  These results were published in Cell Reports.

The research looked at muscle stem cells in mice, in particular a class of stem cells that is normally in a “quiet” mode, jumping into action mainly when needed as “rescuers” to help repair damaged muscle tissue.

Rando’s team noted structural distinctions between young and old cells, and also between young cells that were activated and those that were in the quiescent, or non-active state.

While embryonic stem cells have been extensively studied, Rando said that previously there was no real measurement of the different biochemical properties in these workaday cells that could illuminate whether they were young or old, or healthy or diseased.

“We are trying to understand if it’s possible to understand the age of a cell. We know that old stem cells are less effective in maintaining and repairing tissue,” said Rando, who is the deputy director of the Stanford Center on Longevity and the director of Stanford’s Glenn Laboratories for the Biology of Aging. But it’s not yet clear how the differences in the properties of these cells may play a role in helping them to regenerate the body’s tissues, he added.

From a health and therapeutic standpoint, the research could lay the groundwork for determining if it’s possible to intervene and change the nature of cells as they age. Ultimately it could shed light on why older bones don’t heal as well as young people’s, and what can be done to rejuvenate cells, even temporarily, to repair and heal the body more quickly, a potentially exciting direction in enhancement of stem-cell function.

The research was a follow-on to Rando’s earlier findings demonstrating that old cells could be rejuvenated — made to act like perky, younger cells — when an old mouse’s cells were exposed to the blood of a younger mouse. That was good news – at least temporarily – for the older mouse, but it left the “how” question open.

“Then our question was, are the old cells becoming younger or merely behaving like young cells?” Rando explained. “We said basically that we’ll only believe we are rejuvenating the cells if everything in the old cell looks like a young cell. We wanted to know if we were truly converting them at a biochemical level to being young. Were we really impacting the aging process?”

And thus the key question — “What does it mean to be old or young?”

“We still don’t know in a sense what aging is,” said Rando. To explore the issue, the scientists decided to measure what they could about the changes in a cell’s intrinsic properties as it ages, in this case the proteins that coat the stem cell’s DNA.

With age, they found, the chemical markers on the proteins– called histones – that bind to DNA did change, and thus, “We’re starting to chip away at what will ultimately be a combination of features that determine the age of a cell,” and behind that the cause of aging, Rando explained.

While the cellular genome for any given animal is consistent, Rando hypothesized that over time the cells adopt an altered state in terms of the chemical composition of their DNA/protein complexes. What wasn’t clear was whether those markers really were changing when old cells were exposed to the blood of young mice – in essence reversing the process of aging – or whether the cells somehow had just been prompted to behave younger.

Potentially, the research could have found differences between old and young that were  minimal or non-existent, but the biochemical distinctions the team noted were impressive, said Rando.

The research, if extrapolated with imagination to humans, is bound to conjure images of reversing aging and extending life, but Rando said the implications so far suggest that any cellular rejuvenation is short term – in other words more applicable to healing after an illness or injury.

Further, he said, it’s likely that the longer-term consequences of any potential enhancement of stem-cell function in older people likely would be negative. That’s because older people’s cells are probably slower and less responsive for good reason. It could well be that by dividing more slowly they are meant to slow down the activation of cancer or other latent illness that invades the body as we age.

“We don’t have proof of this but it seems unlikely that there’s going to be no downside to providing the stimulatory signals for cells throughout the body for an older person,” Rando cautioned.

The team now will examine the cellular enzymes that actually are responsible for the markings on the histones, exploring how they may lead from the youthful state to the aged state. Those enzymes, according to Rando, are key to regulating gene expression.