- Aging is a key risk factor for a range of health issues. This is due, in part, to the buildup of senescent cells in a person’s body.
- In recent years, scientists have identified a class of drugs called senolytics. These can destroy senescent cells in laboratory and animal experiments.
- In the recent study, the researchers identified a component of grape seed extract as a potentially effective senolytic, and they used it to extend the life span and healthspan of mice.
In a new study, researchers identified a new drug based on a component of grape seed extract that has successfully extended the life span and healthspan of mice.
The research, which appears in the journal Nature Metabolism, lays the groundwork for further clinical studies to determine whether or not the effects may be reproducible in humans.
Senescence and senolytics
Aging is a key risk factor for many chronic conditions. Scientists believe that this is due, in part, to cellular senescence. This occurs when a cell ceases to be able to fulfill its biological function in a person’s body.
In recent years, researchers have identified a class of drugs called senolytics. These drugs can destroy senescent cells in the laboratory and in animal models, potentially reducing the number of chronic conditions that occur with age and an increasing life span.
In the study, the scientists identified a new senolytic derived from a component of grape seed extract, known as procyanidin C1 (PCC1).
Based on previously available data, PCC1 showed promise at inhibiting the effects of senescent cells when administered at low concentrations and selectively destroying senescent cells at higher concentrations.
To test the effects of PCC1 on aging, the researchers developed three experiments involving mice.
In the first experiment, they exposed mice to a sub-lethal dose of radiation to induce cellular senescence. One group of mice then received PCC1, while the other group received the vehicle that carried the PCC1.
The researchers found that after the mice underwent irradiation, they developed abnormal body features, including significant amounts of gray hair.
Treating the mice with PCC1 significantly reversed these features. The mice who received PCC1 also had fewer senescent cells and fewer biomarkers associated with senescent cells.
Finally, the irradiated mice had worse exercise capacity and muscle strength. However, the mice that received PCC1 saw this reversed and had better survival rates.
In the second experiment, the researchers treated older mice with either PCC1 or a vehicle every 2 weeks for 4 months.
The team found a significant number of senescent cells in the kidneys, livers, lungs, and prostates of the aged mice. However, PCC1 treatment reversed this.
The PCC1-treated mice also had improved grip strength, maximum walking speed, hanging endurance, treadmill endurance, daily activity levels, and balance, compared with the mice who only received the vehicle.
In the third experiment, the researchers looked at very old mice to see what effect PCC1 may have on the longevity of the mice.
They found that mice treated with PCC1 lived, on average, 9.4% longer across their lifetime than mice who received the vehicle.
This equated to a 64.2% extended life span following the treatment.
Furthermore, despite living longer, the PCC1-treated mice did not have any greater age-related morbidity than the mice that received the vehicle.
Summing up the findings, corresponding study author Prof. Yu Sun — of the Shanghai Institute of Nutrition and Health in China — and colleagues say, “We hereby present proof-of-principle evidence that, even when administered in late life, [PCC1] holds prominent potential to remarkably delay age-related dysfunction, reduce age-related diseases, and enhance health conditions, thus providing a new avenue to improve healthspan and life span in future geriatric medicine.”
Speaking with Medical News Today, Dr. James Brown — a reader in aging and metabolism and a member of the Aston Research Centre for Healthy Ageing in Birmingham, United Kingdom — said that the findings provide further evidence for the potential benefit of senolytic drugs. Dr. Brown was not involved with the recent study.
“Senolytics are an exciting new class of anti-aging compounds, often found to be naturally occurring. This study suggests that PCC1 joins compounds like quercetin and fisetin in being able to selectively kill aged cells [while] leaving young and healthy cells alive and well.”
“This study, along with others in this field, looked at the effects in rodents and other lower organisms, and, therefore, there is much work to do before any anti-aging effect of these compounds in humans is established.”
“Senolytics certainly show promise as potentially being the leading class of anti-aging ‘drugs’ that are being developed,” said Dr. Brown.
Mice to humans?
Speaking with MNT, Prof. Ilaria Bellantuono — a professor of musculoskeletal aging at the University of Sheffield in the U.K. — agreed that a key question is whether or not the findings are reproducible in humans. Prof. Bellantuono also was not involved with the study.
“This research adds to a body of evidence showing that eliminating senescent cells using drugs [that] selectively kill those cells — called senolytics — improves physical function with age and enhances the action of chemotherapeutic agents in cancer.”
“It is to be noted that all the body of evidence in this area is in animal models — in this specific case, in mouse models. The real challenge is to test whether these drugs are as effective in [humans]. At the moment, there [are] no data available, and clinical trials are just starting,” said Prof. Bellantuono.
Dr. David Clancy — of the Division of Biomedical and Life Sciences at Lancaster University in the U.K. — said to MNT that the dose levels may be an issue when translating the findings to humans. Dr. Clancy was not involved with the recent study.
“Doses given to mice are often very large compared with what humans can tolerate. Proper senolytic doses of PCC1 in humans may turn out to cause toxicity. Rat studies might be informative; their livers apparently metabolize drugs more like humans’ than do mouse livers,” said Dr. Clancy.
Speaking with MNT, Dr. Richard Siow — the director of aging research at King’s College London in the U.K. — also said that nonhuman animal studies do not necessarily translate into positive clinical effects in humans. Dr. Siow also was not involved in the study.
“I don’t always equate findings in mice and worms and flies to humans, for the simple fact that we have bank accounts — they don’t. We have wallets — they don’t. We have other stresses in life that animals don’t have: dietary, social, work, Zoom calls. I’m sure you can stress out a mouse in different ways, but it’s usually the bank accounts we’re more worried about,” said Dr. Siow.
“It’s a joke, of course, but just to put it in context, you can’t translate everything that you read about in mice into humans. It’s great if you’re a mouse and you want to live to 200 — or the mouse equivalent of 200 — but is that meaningful for man? That’s always a caveat when I talk about animal studies.”
Nonetheless, Dr. Siow said that the findings were significant.
“On the positive side, it’s robust research, and it’s telling us about confirmatory evidence that many of the pathways that even my own research focuses on are important when we consider life span in general.”
“Whether it’s an animal model or a human model, perhaps we need to look at some of these particular molecular pathways in the context of human clinical studies with compounds such as grape seed procyanidins,” said Dr. Siow.
Dr. Siow said that one possibility was the development of grape seed extract as a dietary supplement.
“Having a good animal model with robust outcomes [and a paper] published in a high impact journal does add weight to the development and investment in human clinical studies, whether it’s from the government, clinical trials, or through investors and industry taking this on board, and based on these papers putting grape seed as a nutritional supplement in a tablet.”
“I’m taking nutritional supplements that may not have gone into clinical trials but based on evidence from animals, it adds weight — it gives the consumer confidence that there may be something in this. That’s one degree of translating awareness of nutritional supplements being beneficial in some respects for longevity,” said Dr. Siow.
Healthspan, not just life span
Dr. Siow stressed that the quality of a person’s life was also important, not just the number of years they live.
“If we look at life span, and more importantly healthspan, we need to delineate what we mean by life span. It’s OK that we live until 150, but if we spend the last 50 years in bed, that’s not great.”
“So, rather than life span, maybe a better word would be healthy longevity: You may well extend the number of years, but are you adding life to those years? Or are they meaningless years? And also mental health and wellness: You may be living to 130, but if you are unable to enjoy those years, is it worthwhile?”
“It’s important that we look at the broader perspective of mental health and wellness, frailty, immobility, how we grow old in society — are taking the pills sufficient? Or do we need more social care? If we’re living into our 90s, 100s, 110s, is there support in place? Is there government policy?”
“If these pills are helping us and we are getting into our 100s, what can we do to improve the quality of life — not just by taking more pills? There’s only so much you can do with grape seed and pomegranate and so on,” said Dr. Siow.
Prof. Bellantuono said that the study’s findings could be particularly valuable for developing clinical trials involving cancer patients receiving chemotherapy.
“The general challenge with senolytics is to identify [who] will benefit, and how to measure the benefits in a clinical trial.”
“In addition, as many of these drugs are most efficacious in preventing a condition rather than treating it when it is diagnosed, the clinical trials could last years depending on the conditions, and this is too expensive to do.”
“However, in this specific case, [the researchers] have identified a group of patients [who] will benefit from this: cancer patients undergoing chemotherapy. In addition, as it is known when the formation of senescent cells is induced — that is, with chemotherapy — and when the effects they cause on the tumor and physical performance occur — that is, weeks to [a] few months — this is an excellent example where a proof-of-concept study testing the efficacy of senolytics in patients could be performed,” said Prof. Bellantuono.
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