James Kirkland's Quest to Extend Health span

“It’s much better to live till you’re 90 feeling you’re 50, than to live to be 180 feeling like you’re 180,”

James Kirkland’s mission is, in his own words, to ‘add life to years, not years to life’. His fascination for ageing comes from a young age, when he first noticed how his beloved grandparents looked different from his parents. Later, he turned that budding interest into a research career when, as a clinician, “he got tired of prescribing better wheelchairs, walkers, and incontinence devices” for his geriatric patients. Instead, he would rather be prescribing something that would slow down or even reverse ageing. 

In 2015, Kirkland and his team at the Centre on Aging at the Mayo Clinic, published a paper that showed for the first time how we might achieve that. The study demonstrated how certain drugs — so-called senolytics — seemed to delay, prevent, and alleviate chronic disease in frail old mice.

This was a breakthrough in ageing research, one that had taken Kirkland more than ten years to achieve. What first spurred his interest was a 2004 study that showed that a caloric restricted diet slowed down ageing in mice. Researchers showed that this was achieved by delaying the accumulation in the body of the so-called senescent cells. These cells build up in the body as we age, secreting molecules that damage and kill other cells around them. This set Kirkland on a quest to find chemical compounds that could eliminate senescent cells. For years, they tried everything, from toxic antibodies to drug screening massive libraries of chemicals. Nothing worked until, in 2013, he made an observation that turned the problem around: why could senescent cells damage other cells around them, but not other senescent cells? What protected them from their own damaging secretions? It turned out that senescent cells had specific molecular mechanisms that acted as protection. That was Kirkland’s aha moment: if he managed to sabotage those mechanisms, he would be able to force the senescent cells to commit suicide.

Using bioinformatics, Kirkland’s team originally identified over 20 different senolytic (a portmanteau of “senescence” and -lytic, “destroying”) compounds that could achieve this. His 2015 study showed that two such compounds, dasatinib and quercetin, could effectively and selectively destroy senescent cells, while leaving non-senescent cells intact, in old frail mice. Furthermore, these drugs also seemed to alleviate a range of symptoms associated with old age, improving cardiac function and delaying osteoporosis. 

Crucially, these senolytic drugs are also flushed out from the body in a matter of days, meaning that while senescent cells were killed, the body’s ability to make new ones was not impaired. This is important: despite their role in making us age, senescent cells also play an important role in protecting us against cancer, fighting infections and healing wounds. “You don't want to interfere with senescence cell generation or cancers occur,” Kirkland says. “We call it a hit-and-run approach. like antibiotics where you're treating a urinary tract infection with a single round of antibiotic, you can hit them once and then wait.” 

Many other studies followed. In 2018, Kirkland and his team published a paper in Nature that showed, for instance, that if senescent cells were transplanted into middle-aged mice, those mice would die an early death from diseases associated with old age. “There's a threshold phenomenon,” Kirkland says. “If you transplant only 500,000 senescent cells, nothing happens. If you transplant a million senescent cells into a middle-aged mouse, these animals will get frail, they'll die earlier. Not just any one of them, but all of them as a group.” Once the number of senescent cells exceeds that threshold, this starts interfering with the body's capacity to remove senescent cells, resulting in accelerated ageing. This is known as antagonistic pleiotropy. "These are processes that are beneficial in younger individuals, but, if they continue, will harm old individuals," Kirkland says. "Natural selection only cares if you're able to reproduce and keep the offspring alive."

Kirkland also found that metabolic complications from obesity and diabetes — which are associated with an accumulation of senescent cells in fat and adipose tissues — could be forestalled by senolytic drugs: obese mice on senolytic drugs showed improved response to insulin and restored kidney function. In 2019, Kirkland reported similar results in humans, in a small clinical trial with diabetic and obese patients and obesity. These patients were given a brief course of dasatinib and quercetin. Blood tests and fat biopsies showed that by day 14 the number of senescent cells had decreased in adipose tissue, accompanied by reduced inflammation and less scarring. This was another milestone in ageing research, as the first study demonstrating the efficacy of senolytics in humans. 

Currently, Kirkland is running 27 clinical trials, involving patients with diseases like Alzheimer’s, osteoarthritis, childhood cancer survivors, bone marrow transplant survivors and diabetic patients. “We’re even going to measure blood and urine from astronauts at the International Space Station,” Kirkland says. “It appears that zero gravity, g-forces and space radiation can result in DNA damage, and many astronauts are developing tumours and earlier onset of Alzheimer’s disease.”

While most of the trials — 15 — involve senolytics, others are studying pharmacological compounds like metformin and rapamycin, which have been shown to directly tackle different fundamental ageing-related processes from senescent cells. This approach is underpinned by what Kirkland calls the unitary theory of fundamental ageing processes. “We have the view that the different fundamental pillars of ageing processes are highly interlinked,” he says. “If one progress goes wrong, the others are affected. They interact with each other very much. The various interventions that target these fundamental ageing processes, if they affect one, they tend to affect all the rest.” 

This theory seems to be corroborated by data from preclinical trials showing that senolytics and other compounds indeed appear to work better when combined. “It looks like they might be synergistic,” Kirkland says. “I think over the next five years there will be the notion of combining disease specific interventions, with interventions that target fundamental ageing processes.” His hope, of course, is that targeting these fundamental ageing processes will result in preventing and delaying the syndrome of chronic diseases associated with old age, from frailty to cognitive impairment. “We’re no longer dealing with the old-fashioned drug development paradigm of one drug, one target, one disease here,” he says. “We're using drugs that have more than one target. We're targeting a network of pathways and we're going after multiple age-related conditions, not just one disease.”

For now, with more than a hundred senolytic compounds identified and 27 clinical trials underway, Kirkland urges caution. “It will be roughly three to five years before we know if some or any of these clinical trials work. I’m touching wood,” he says. “As you're aware, ninety percent of clinical trials fail. That's why we're doing so many things in parallel instead of in series.”

It’s still too early for the public to be taking these compounds or for physicians to be prescribing them, he says.” I lay awake every night, wondering if we're going to hurt someone in one of the clinical trials,” he says. “I worry about this, because we’re playing with very fundamental biological processes.” 

Still, if he is right, James Kirkland’s pioneering research might well completely upend our understanding of ageing. Just don’t call it “anti-aging research”. The process of ageing, he points out, starts from the time of conception and it’s not something you want to stop from occurring. His ultimate aim, instead, is not so much to extend lifespan at all costs, but to extend health-span — the period during life when people are able to live independently, free of pain and disability. “It’s much better to live till you’re 90 feeling you’re 50, than to live to be 180 feeling like you’re 180,” he said.