Ageing is the biggest risk factor for chronic illness
But how and why we age is incredibly complex
This is the story of a scientist searching for the universal rules of ageing
With the spool of thread in her hand, the Ancient Greek figure Clotho was able to decide the fate of the mortals on Earth. Clotho had the ability to start and restore life, bringing back into the world those who died by unjust means and choosing when people would be born.
Her life-giving mythology is the reason she lends her name to a peculiarity of biology; the α-klotho protein. An increase or decrease in the abundance of this protein seems to lengthen or shorten, respectively, the lifespan of mice and other animals. "Its numbers also seem to be low in people with conditions like Alzheimer's disease, and other neurocognitive disorders," adds James Kirkland, professor of medicine at Mayo Clinic. Kirkland leads the Translational Geroscience Network, an international team searching for potential anti-ageing treatments.
The mechanism by which α-klotho seems to slow down ageing is not fully understood, but it is thought to be linked to the suppression of insulin. While insulin is essential to healthy functioning, too much insulin might be associated with premature ageing.
The protein is just one example of a mystery of biology that could revolutionise how we think about ageing if we were able to unlock it.
How and why we age is a complex picture. Across the full spectrum of life on Earth there are a few examples of species that appear to defy ageing. The hydra, a freshwater cousin of jellyfish, seems to be able to regenerate indefinitely. If cut into pieces, it will regrow into many individuals, like the serpent from Ancient Greek mythology that could regrow its heads, and from which it takes its name.
Unlike the hydra, ageing is inevitable for humans whether we like it or not. But we are starting to reveal more about how we age, and how we could live well for longer, by unpicking some universal rules. By studying what happens to us as we age, we might open the door to a whole new understanding of lifespans and healthspans, hopes Kirkland.
Kirkland thinks about the causes and effects of ageing like an hourglass: At the top are many causes, like genetic and environmental factors, that increase the rate at which we age.
Environmental factors could include pollution, ultraviolet radiation or diet, while any number of different genes might predispose us to ageing faster or slower.
At the bottom of the hourglass are the many effects of ageing - diseases that tend to arise as we get older like cancers, dementia and Alzheimer's, osteoporosis, immobility and frailty.
Between these two is a pinch point, at which are the fundamental pillars of ageing. "Hundreds of diseases, disorders, conditions and so forth are arguably causally related to or associated with [the fundamental pillars of ageing]," says Kirkland. "They appear to all be interlinked to some extent, such that if you target one of them, you tend to affect all the rest."
Targeting one pillar to see improvements in the others is referred to as the "unitary theory of fundamental ageing mechanisms". Interventions that target one of the pillars, cellular senescence, for example, tend to result in reduced inflammation, decreased fibrosis, and restoration of the microbiome in animal trials. "It seems logical to target that pinch point," adds Kirkland.
Exactly how many pillars of ageing there are varies depending on which geriatrician is asked. Kirkland favours thinking of them as four; inflammatory processes, issues with molecules, issues with progenitor cells and senescence.
The Four Pillars
The first of those four pillars, inflammatory processes, you might be familiar with as the reddening of skin or heat and pain around an infection. But inflammation affects all cells including internal organs. It is associated with fibrosis, or the thickening or stiffening of tissue, which ultimately can lead to organ failure.
The second pillar includes errors and changes in various large molecules and sets of molecules, like DNA, proteins (which notably are linked to diseases like Alzheimer's or Parkinson's), and fats.
The third pillar involves progenitor cells, which have the ability to turn into specialised cells that are then able to turn into new tissue. These cells regenerate tissues after damage, or as tissues naturally turn over, so are very important for healing.
One such example is when progenitor cells give rise to cells that break down bone. These cells increase as we age. Another kind of progenitor cell that gives rise to cells that make new bone, decreases with age. This combination is one of the causes that underlies osteoporosis, for example. "The same thing is true of progenitors in multiple tissues, like the liver, kidneys, heart, brain, lungs and skin," says Kirkland.
The final pillar is the centre of Kirkland's and his colleagues research; cellular senescence.
We are constantly rebuilding and replacing our cells. This renewal keeps us healthy and helps us to repair damage to our bodies. Cellular senescence is a key part of this renewal process. A senescent cell is one that stops dividing but rather than dying off, it signals to the immune system that it needs to be destroyed, before it is replaced with a new one.
Senescence, meaning "to grow old", has a key role to play at a cellular level in humans and other species; it might prevent cancerous cells from proliferating, or help to heal wounds. "If you stop an organism's cells’ ability to become senescent, they become filled up with cancer pretty quickly," says Kirkland. "You don't want to stop cells from becoming senescent, it would cause all kinds of problems."
Senescent cells are usually only a fraction of the number of cells in our bodies, but as we get older they tend to linger, taking longer to be cleared by the immune system. “Once you're above a threshold, the rate of formation of new senescent cells exceeds the ability of the immune system to clear them,” explains Kirkland.
If these cells linger for too long they can cause a whole host of issues – they can mutate coronaviruses and cause inflammation, and some might even cause cancer.
Kirkland and his colleagues' research focuses on finding drugs that help the body to clear lingering senescent cells, which might help to treat or even prevent diseases of age. By targeting senescent cells, rather than targeting individual diseases, it might be possible to improve multiple health conditions, with a substantial societal and economic benefit.
A few different approaches are currently being investigated, including repurposing two cancer drugs. Kirkland found that these two drugs seem to be effective in different tissues but are most effective when used in a specific combination.
Tests on mice show that this combination can increase speed, endurance, strength and extend lifespans by 36%.
"It looks like in animals if we get rid of persisting senescent cells we can delay, prevent, alleviate or treat the bulk of conditions that cause most morbidity and mortality," he says.
Kirkland is excited by the promise of drugs called senolytics, which help the body to clear persistent senescent cells. Some of these senolytic drugs, like the one Kirkland describes above, are repurposed from treating other diseases like cancer.
He compares it to the zeitgeist-changing discovery of antibiotics, which opened up a whole new field of treatments. But, translating animal trials into humans is a big step, and he warns against over-promising. "Even with the best drugs, we think there might be a 5-10% chance [of success in human trials]," he says. "Usually, there will be downsides. We don't know what they are yet."
In-human trials of senolytic drugs are underway, but the safety of these drugs is not proven, so there is some way to go before they might be available to patients. Which intervention is best for which person is also still unclear, too, says Kirkland. "I think, unfortunately, people have to be a bit patient."
Because there's great diversity in the rate at which fundamental ageing processes occur in different populations around the world, it is hard to predict how diverse patients might react to these new drugs. There are certain conditions that are associated with greatly increased longevity. For example, short stature is associated with lower levels of growth hormone and longer lifespans, possibly because people with less growth hormone tend to develop less in the way of cancers and less cellular senescence, says Kirkland.
Kirkland hopes that his research in senolytics helps not only to promote long life, but healthier life. "When people go to their physician they ask to feel better, not live longer," he says, speaking generally about how people engage with healthcare.
There are meaningful implications to extending the length of time that someone lives a healthy life – known as healthspan. "The last year of life of a person who dies over 100 costs the health system 30% less than what it costs the health system for a person who dies in their early 80s for their last year of life," he says, meaning that people who live for a long time seem to have healthier lifestyles, more independence and less reliance on the health system.
"There are economic benefits to this as well," says Kirkland. "Maybe people will continue working for longer, contributing more to society – this could arguably have a big benefit in [developing countries]."
At this stage, senolytics research has some way to go, but the science is promising, and as we start to unspool the thread of life we might be able to find answers to other medical mysteries that have escaped researchers to date.
When people go to their physician they ask to feel better, not live longer
