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Forever young: Senescent cells and secret to stopping ageing

Turning back the clock on senescent cells could switch off the ageing process… but there’s a catch.

Advances in living standards and medicine over the past half century have pushed the life expectancy of the world population as a whole up from just 48 years in 1955 to around 71 years today (with of course huge variations between and across countries).

The population pyramid too has been tipped on its head, with the proportion of the world’s people over 65 years projected to grow more than four times as fast as those below this age between 2005 and 2030. The proportion of the very elderly – people over the age of 85 years – is growing fastest of all.

The ageing of the world population is one of the biggest challenges of the twenty first century – “up there with climate change” for its potential to disrupt societal order, says Tom Kirkwood, Associate Dean for Ageing at Newcastle University, because the extraordinary progress in adding years to life has not been matched by progress in adding life to years.

A 5-year-old in the UK today can expect to live, on average, to around 80 years. But experience shows that their last 15-20 years are likely to be dogged by ill health and growing dependency on family, friends and social services, which are already struggling mightily to cope.

On a personal level, the prospect of prolonged decrepitude scares many of us as the reality of old age becomes ever harder to ignore. But the good news is that long years of infirmity are not inevitable. Gerontology – the science of why and how we age – focuses primarily on increasing our “health span” (as opposed to our lifespan), and researchers in this field are making some exciting discoveries.

One cause for optimism is the fact that many of the conditions associated with advancing years – from stiffening joints, thinning bones and waning energy, to heart failure, cancer, stroke, dementia and the gradual loss of hearing and eyesight – have common roots.

The biggest single risk factor for them all is old age itself, and it follows that anything we can do to slow or ameliorate the ageing process will reduce the risk of developing any of these diseases.

At the cutting edge of the effort to do so is the study of “senescent cells”. Our bodies grow, develop and repair themselves through a process of cell division, during which a cell’s genetic material is copied and a daughter cell is hived off from the mother.

Because errors in copying the DNA are liable to creep in over time, leading to mutations that might be harmful or even fatal, dividing cells have a finite lifespan, as measured by little caps called telomeres on the ends of their chromosomes.

But cells that have reached the ends of their replicative life don’t die, they simply “senesce”. The process is not synonymous with ageing, as their name might imply; senescent cells are generated all the time, from babyhood onwards, and are part of a mechanism to protect us from cancer caused by cells with corrupted DNA that can run amok.

In the normal course of events, senescent cells are cleared away regularly by the immune system. But as our immune system itself weakens with age, senescent cells accumulate and begin to damage the tissues. These cells are dysfunctional and potentially harmful.

As they continue to metabolize, they secrete substances into their environment that chew up the collagen, the stuff that holds our cells together. Collagen fibers are long and elastic and keep our skin firm and young; as it degrades it leaves wrinkles and saggy bits.

The degraded collagen also leaves spaces that give precancerous cells that may have been lurking there, held in check by firm young tissue, room to proliferate. And the secretions from these no-longer-dividing cells encourages inflammation – constant, low grade, below-the-radar excitation of the immune system – that is one of the key driving forces of ageing.

Scientists are investigating a number of strategies for dealing with senescent cells. They have found drugs that can wipe them out altogether; and they’ve also found ways of rejuvenating these cells, turning back the clock so they can divide again and resume normal function.

I’ve watched them do so under a microscope, and it was awesome! The ones I saw were rejuvenated with the use of a drug, but tinkering with the telomeres that mete out their lifespan can have the same effect.

There are, however, serious drawbacks to each of these strategies. It turns out that senescent cells have some beneficial attributes too. They secrete substances that promote efficient wound healing, and clearing them from the system greatly inhibits tissue repair.

Also, administering a drug to clear senescent cells in a very old animal (or person) with a high accumulation of such cells could be catastrophic (no need to spell out the possible gruesome consequences!) And the drawback with turning back the clock so that senescent cells are able to divide again is that this would override our bodies’ anti-cancer mechanism, possibly giving free rein to corrupted DNA.

This is a prospect that “worries the socks off” Lynne Cox, Associate Professor of Biochemistry at Oxford University, who showed me the rejuvenated cells under the microscope. Experiments with this strategy in ageing mice have shown marked rejuvenation, says Cox.

“The muscle mass increases; the gut shows improvement; I think even their brain size increased. But if the mice had a precancerous tumour, it became very aggressive very quickly.”

Researchers are working to refine the drugs and techniques to a point where they can control senescent cells to preserve their beneficial behaviour while minimizing the harm they can do. Such prospects are a long way from the clinic.

But the great value of the work on senescent cells so far is that it demonstrates clearly that ageing, though inevitable, is “plastic”, not fixed. It can be altered.

Inspired by this profound insight, researchers in many areas of gerontology, from genetics, immunology, and nutrition, to stem cells, blood and neuroscience, are looking deep into our biology and revealing tantalizing clues to what might be possible in minimizing the miseries of old age.

Itching to take the fruits of their research forward towards the clinic, a group of gerontologists have already won approval in the USA for the first ever trial of a drug aimed at treating ageing per se, rather than any one of the individual diseases associated with ageing. It will start as soon as the researchers have raised the funds.

No one is promising a silver bullet – ever. Rather this trial is aimed at proving the principle that the best way to ensure health and independence deep into old age is to address the phenomenon as early as possible, rather than when serious pathology has developed.

It makes such obvious sense, but it will take a sea change in medical and political thinking to make a “healthy” natural process rather than an obvious disease the primary focus of attention.

Source: https://www.sciencefocus.com/the-human-body/forever-young-senescent-cells-and-secret-to-stopping-ageing/

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