Aging is something that happens to all humans.
But few people consider it a disease in the traditional sense because it is universal and considered natural and inevitable, while diseases are seen as abnormal things with negative impacts on health and life.
But what if many aspects of aging, like hypertension, are in fact preventable, retardable and treatable? This would seem to make the process much closer to the way many people think about diseases, in so far as they think about them at all.
That is what gerontologists are examining, and there is evidence to suggest that solving aging could have massive repercussions on longevity.
“Rather than going after the 200 or so age-related diseases- by which I mean diseases for which your primary risk is your number of birthdays – individually we target their causal mechanisms directly and hit multiple age-related diseases and impairments simultaneously. It is simply the idea that since the physiology of ageing is the primary cause of most late-life chronic disease, targeting that physiology directly will prevent it happening,” said Professor Richard Faragher, Professor of Biogerontology at Brighton University.
Two areas of research are providing the gerontology community with the most promise: dysregulated nutrient sensing and cell senescence.
Dysregulated nutrient sensing is one area of research that is providing gerontologists with promise regarding the management of aging as a disease. Key here is the concept of target of rapamycin (mTOR), which acts like a cellular fuel gauge – sensing when nutrients are plentiful and telling the body’s cells to grow, divide, and build. But when this system stays switched on for too long, as it often does with aging, it can lead to cellular wear and tear. By learning how to gently dial down this signal, researchers hope to slow the aging process itself, not just its symptom.
Efforts to implement this ‘dialling down’ showed promising results from tests conducted on mice in a paper published back in 2009, but it was the findings from a study conducted on humans, published in a 2018 paper from Joan B Mannick, et al, that really got the community’s juices going.
“Mannick’s work gave a couple of hundred older people an eight-week, low dose treatment with a drug like rapamycin and then she simply gave these people a flu vaccination. Many older people cannot respond to vaccinations because their immune systems are senescent but all these people responded, and were protected against multiple strains of flu not just the strain they were vaccinated against. These people were followed through for a year, keeping infection diaries. Their rates of infection was roughly half that of the control group,” said Faragher.
The second mechanism relates to cellular senescence – cells that age and stop dividing but do not die. Over time, large numbers of old (or senescent) cells can build up in tissues throughout the body which has deleterious effects.
Scientists say that senescent cells want to be found by one’s immune system, so they can be killed. But the immune system is also made of cells, which can themselves become senescent, which means the immune system is less effective. For example, a senescent cell in a 20-year-old has a much higher likelihood of being found and destroyed than it does in a 70-year-old; the result of both an increased generation of senescent cells because someone is older, and reduced clearance because they are older means that senescent cells start to build up exponentially in the body.
Another study on mice from Baker, et al, published in 2016, illustrates the impact that the removal of senescent cells had on the study population.
That leads to an inescapable conclusion.
“If you remove senescent cells, you dramatically improve health and you dramatically lengthen lifespan in rodents. The study from Baker showed that the improvement was up to 27% depending on the genetic background of the mice and showed a lifespan increase of up to 35% depending on the sex,” said Faragher.
Now it is a case of proving the concept in humans. Senolytics – the class of drugs designed to selectively eliminate senescent cells – saw encouraging results from a trial conducted by Justice, et al, the findings of which were published in 2019, which targeted idiopathic pulmonary fibrosis specifically.
Now, there are multiple trials in the pipeline, some of which are at the recruiting stage, all targeting certain diseases, from childhood cancer through to Alzheimer’s. While approximately 90% of clinical trials fail, Professor Faragher remains optimistic because these trials are different.
“This is just a numbers game now. The more clinical trials you put down range, the more likely it is that something will work,” he said.
“And the other thing that makes these numbers look better is that these trials are working with actual drugs, not molecules that we’re trying to clear out as drugs. Whilst over 90% of all clinical trials fail, roughly 60% of all drug repurposing trials succeed. So, this is really quite potentially positive.”
Implausibility of radical life extension in humans in the twenty-first century, an article in Nature Aging from Olshansky, et al, says that “survival to age 100 years is unlikely to exceed 15% for females and 5% for males, altogether suggesting that, unless the processes of biological aging can be markedly slowed, radical human life extension is implausible in this century”.
But what if fundamental ageing mechanisms can be, and then are drugged?
“If you make the assumption that fundamental ageing mechanisms are druggable, and they are, then linear rates of medical advance become quite sufficient to sustain long term, linear increases in human life expectancy,” said Faragher.
Pensions and life insurance actuaries will want to incorporate this into their longevity models, of course, and a paper co-authored by Faragher, Scanning the horizon: integrating expert knowledge into the calibration of stochastic mortality models helps with that.
And they will need to. In stock markets, a black swan event is one which moves the market significantly. Many use six standard deviations, meaning that the S&P 500 at 5,000 would fall 9% to 4,500 in a single day. Would a breakthrough in Geroscience be the longevity ‘black swan’ for the pension and life insurance world? And if, so, when might this occur?
“The primary barrier to rapid progress today is not that we don’t understand how the process works: It’s been historic underfunding. We spend far, far more on siloed biology of disease than we ever did with the biology of ageing, for example,” said Faragher.
“I obviously don’t know when this might happen. But, make no mistake, there is potential for developments in geroscience to significantly disrupt current mortality assumptions.”
