James Kirkland, MD, PhD, on expanded senolytics, geroscience, and translation (Part 2)

Dr. James Kirkland’s research explores how cellular aging impacts a range of age-related and chronic diseases. In a recent interview, Dr. Kirkland explains what senescent cells are, how they impact the aging processes, and how his lab’s research is pushing toward treatments to remove these cells. This research holds the promise of preventing, delaying, and alleviating multiple diseases, including cancers, dementias, diabetes, arthritis, and more.

In the 2nd installment of a two-part Ask the Expert series, Dr. Kirkland speaks to the future of senolytic therapeutics, new studies in humans, and a geroscience approach to examining how cell senescence impacts the multiple chronic diseases that are predisposed to by aging processes.

Have senolytics been shown to prevent, delay, or alleviate age-related disorders in preclinical models?

We, and others, have done studies with the senolytic drugs in mice, rats, and monkeys. Over 40 conditions in mice that model various disease states in humans appear to be delayed, prevented, or alleviated. We also found that some senolytics will increase median lifespan if given in older animals that have senescent cells (you wouldn't want to give these drugs throughout life to individuals who don't have senescent cells.) We found that we could increase remaining median lifespan in mice with some of these agents, and also delay onset of age-related disorders and diseases as a group.

How do senolytics relate to geroscience (the application of aging biology principles to diseases)?

The mice died later of every kind of age related disease that we know of — it wasn't one particular disease, it was all of them. This would argue for the geroscience hypothesis, which holds that fundamental aging processes might be root cause contributors of many of the chronic disorders and diseases that account for the bulk of health expenditures, morbidity, and mortality. Conversely, we found that if we transplant small numbers of senescent cells into healthy middle-aged mice, we made them effectively age faster. They became frail. They died earlier and they died earlier of all age-related diseases, not any particular one. A very small number of senescent cells was sufficient to do this.

This sort of meets Koch's postulates that were used to prove that bacteria cause infections and as the basis for developing antibiotics. You put in the bacteria and you cause the disease. If the bacteria are not present, the disease isn't there. If you remove bacteria in individuals with the disease, you alleviate the disease. The same thing appears to be true of senescent cells. The strategies for developing some senolytics have been much more akin to developing antibiotics or antivirals than they are to drugs where you're treating, for example, high blood pressure and where you follow a single drug, single target, single disease approach.

With senolytics, we’re going after a network of targets. Our main target is senescent cells, not a molecule, not an enzyme, not a receptor. We're using a “hit and run” approach, using combinations of drugs or drugs that hit multiple targets, and we're going after every age-related condition to determine if we can delay, prevent, or alleviate them. This seems to be the case for a range of senolytics now, and it seems to hold across a range of disease states. In experimental animals, these agents also alleviate what we call the geriatric syndromes, including frailty, sarcopenia (age-related muscle loss), mild cognitive impairment, and so forth, in aging animals. Clinical studies are now underway to look at these conditions. Senolytics also appear to improve resilience in individuals with a burden of senescent cells. For example, the ability to respond and recover from an infection or surgery or even to respond appropriately to a vaccination is enhanced. There are trials underway looking at these resilience issues, especially factors related to the current COVID-19 pandemic.

Tell us about a few of your smaller studies with senolytics.

There are at least a dozen clinical trials currently underway. Early results from a couple of them were published just over a year ago. In one of them, there's a condition called idiopathic pulmonary fibrosis, which is a very difficult disease to treat in humans and occurs in the elderly. It's associated with accumulation of senescent cells in the lungs and quite a bit of frailty. In a very small open-label pilot study, Mayo Clinic, with collaborators at the University of Texas (San Antonio) and Wake Forest University, found that frailty in these individuals could be alleviated by a short course of senolytics. While this was in only a very few subjects, open-label, and there was no true randomization or a placebo control, we did find frailty was alleviated. It didn't go on long enough to look at lung function as we only gave a few doses to look at that first frailty outcome.

In a second very small trial, we did biopsies of fat tissue in younger individuals who are obese and diabetic. We found obesity is associated with incredible senescent cell accumulation and with early onset of age-related diseases. We looked at fat tissue biopsies and blood samples taken just before senolytics were given and 11 days after completing a 3-day course of senolytics, long after the drugs are no longer present because they have a very short elimination half-life and are gone from the body within a day and a half. We found that 11 days after the last dose (day 14) there was a decrease in senescent cells in the fat tissue of these subjects, a decrease in inflammation in their fat tissue, and a decrease in fibrosis. Between day zero and day 14, blood markers for senescent cells were substantially decreased. This showed to us that at least this one particular senolytic regimen clears senescent cells from humans to an extent. It's the 30 to 70% of senescent cells with a SASP that are trying to kill other cells that are killed. The other senescent cells, what we call “helper senescent cells”, which aren't tissue-damaging, are not affected by these drugs. The way these drugs work is by allowing cells to kill themselves instead of killing cells around them. So “helper”, or beneficial senescent cells in our view, are not actually targeted by these drugs.

Are placebo-controlled, double-blind trials with senolytics underway in humans?

Now, clinical trials are underway for a range of conditions. These trials are placebo-controlled and double-blind. For example, bone marrow transplantation survivors who develop an accelerated aging state after their bone marrow transplant because of the high doses of chemotherapy they get. We're looking in survivors of childhood cancer treatment with St. Jude Children’s Cancer Hospital. These are people who were treated for leukemia or other cancers as children. Now that they're in their thirties and forties, some of them are developing an accelerated aging state. They're getting diabetes, osteoporosis, frailty, and muscle weakness, some of them even get Alzheimer's disease. So in that population, we're trying different senolytic regimens compared to a placebo.

There are also trials underway on Alzheimer's disease and in frailty in elderly women who have decreased gait speed. There are a couple of trials for coronavirus because it's specifically the elderly and people with obesity, diabetes, atherosclerosis, and other senescence-related conditions who get very sick with the coronavirus. We’re also looking at trying to rehabilitate organs donated from older donors before they're put into younger recipients. I mentioned before that transplanting senescent cells causes problems, and we found with collaborators at Harvard that indeed transplants from old to young animals can spread senescence to the young animal. We currently throw away 35,000 kidneys a year that are donated, from car accident victims for example, if they're older because we know that the kidneys don't do very well. We're attempting to see if by treating those kidneys before they're transplanted, we might be able to rehabilitate them and get better outcomes for recipients.

We also have continuing trials in idiopathic pulmonary fibrosis, continuing trials in diabetes, obesity, renal dysfunction, age-related osteoporosis, osteoarthritis and a number of other conditions. The main thing that we're looking for across these trials is safety and tolerability.

Do we know senolytic drugs are safe for humans yet?

We don't know if these drugs are safe. We would caution the general public not to take senolytic drugs. We're playing with a very fundamental process in our bodies. There could be a significant downside. We don't know yet. We haven't seen that so far, but it doesn't mean we won't see it. So the only time these agents should be used is in the context of carefully controlled clinical trials that are monitored by physicians, by the Food and Drug Administration (FDA), and by institutional review boards (research ethics committees). I don't think the general public should be attempting to take these drugs unless and until we know that they're safe, and there’s a way to go before we're at that point.

You’re both an AFAR grantee and its incoming President-Elect. You’ve also mentored many junior investigators who have received AFAR grants. What is the major contribution of AFAR to the field of aging biology and geroscience?

I think there are too many things for me to count! AFAR helped me and many others to start careers. AFAR has provided funds for investigators in strategic areas. They’ve picked the right areas over the years and done a really good job with that. They've got very knowledgeable people who review the grants and award them, and they use a peer review process. It's very, very well done.

In addition to that, AFAR has done tremendous work in raising awareness of the need to study the biology of aging and how that relates to potential treatments for people to improve the health span and their happiness throughout their lives. It's turning out that some of these interventions are being used in children that have been discovered with respect to the biology of aging. We start aging from the time of conception, and a lot of disease states are predisposed to by the processes that AFAR has invested in studying.

AFAR has been at the forefront of translating interventions that look effective against what we call the “Hallmarks of Aging," or the basic biology of aging, into clinical application. I think the next decade especially could be incredibly exciting as these various interventions, not just senolytics, but things like Metformin, the rapalogs, and other interventions that AFAR has supported and developed, are moving into clinical trials. They could have widespread ramifications. AFAR has made this known to our political leaders, to leadership in the scientific community, to deans of various universities, and as well as the general public. I think AFAR has done a tremendous job in raising money to support the field, advocating for the field, and providing thought leadership.

Read Part 1 of Dr. Kirkland's Ask the Expert Interview here.