Longevity

5 Possible Anti-Ageing Interventions That Have Been Tested In Humans

Posted on 15 February 2022

We know it’s possible to extend the lifespan of certain animals using relatively simple interventions. The maximum lifespan of rodents can be increased by up to 50% through calorie restriction. Various drugs already approved for use in humans, like the immune suppressing rapamycin, have also been shown to extend maximum lifespan in animals.

These experiments are important, as they suggest that the biological process of ageing is malleable, and that we might one day be able to slow ageing in humans. So far that hasn’t happened, in large part because the kind of experiments that might prove a slowing of the ageing process in humans simply aren’t feasible. We can’t take a group of human babies, put half of them on a calorie restricted diet for their entire lives, and see what happens. Instead, the best scientists can do is to study factors that could make good surrogates for how quickly a person’s biological age is increasing. These include factors such as the extent of damage to one’s DNA and the length of one’s telomeres, but also more functional measurements such as walking speed and balance. We call these surrogates biomarkers of ageing.

So, of all the interventions shown to extend lifespan in animals, which ones have actually been tested in humans? And, more importantly, what are their effects?

Calorie Restriction

What is it?

Calorie restriction (CR) is a reduction in calorie intake that doesn’t cause malnutrition. Though it doesn’t strictly count as calorie restriction, fasting (the complete elimination of calorie intake for an extended period) has comparable effects to calorie restriction.

How does it work?

Aside from the health benefits associated with weight loss, CR may affect the ageing process by triggering certain molecular pathways within cells. Cells adapt their behaviour in response to the availability of nutrients in their environment. If nutrients are scarce, this puts cells into a kind of ‘survival mode’. Faced with insufficient nutrients to support growth and division, cells will instead dedicate what energy they have to repairing themselves and surviving until nutrients become available again. This includes repairing their DNA and clearing out damaged cellular components.

What does the human evidence say?

In humans, randomised trials have found calorie restriction to have many beneficial effects on human health, including:

A recent study did investigate the effects of CR on one of our most promising biomarkers of ageing – DNA methylation. DNA methylation refers to the addition of molecular ‘tags’ to the DNA molecule, which can change the way the DNA is read. These are referred to as epigenetic changes. The distribution of these tags changes throughout life, allowing scientists to estimate the ‘epigenetic age’, an approximation of the true biological age of an organism, by looking at which DNA sites have been methylated. In the study, which has not yet been peer-reviewed, researchers looked at DNA methylation in 197 participants of a randomised controlled trial of long-term CR. Using six different metrics for relating DNA methylation to biological age, they found the effects of CR to be limited, with only one metric showing a statistically significant association.

This would suggest that CR improves healthspan (the length of time a person remains in good health), but may not slow the pace of ageing. However, we need much more evidence before this can be confirmed.

NAD+ Supplements

What is NAD+? | Why Is It Important? | NMN.com
Molecular structure of NAD+
Source

What is it?

Nicotinamide adenine dinucleotide (NAD) is a molecule that plays an essential role in converting the nutrients we obtain from food into a form of energy that our cells can use. This process takes place within the mitochondria, the power plants of the cell. As the mitochondria accumulate damage and become less efficient with age, NAD within the cell begins to become depleted. Since NAD is necessary for many other processes within the cell, including repairing the DNA, depletion of NAD is suspected to play an important role in the ageing process. However, it is possible to increase NAD levels by consuming compounds that cells can use to synthesise new NAD.

How does it work?

By supplementing with a precursor to NAD, such as nicotinamide riboside (NR), the amount of new NAD being synthesised by cells can be increased, meaning that there is more NAD available to the cell. Based on what we know about NAD, this should help prevent certain processes thought to play a fundamental role in ageing, such as DNA damage and mitochondrial dysfunction.

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. -  Abstract - Europe PMC
Functions of NAD+
Source

What does the human evidence say?

Studies have generally found NAD precursors to be safe in humans at recommended doses, and suggest that supplementation can increases cellular NAD levels in a dose-dependent manner. However, results from studies into the effects of NAD precursors on human health have been relatively unimpressive.

  • Several studies found no improvements in metabolic function, exercise capacity, liver or kidney function for NR when compared with placebo.
  • One study found no evidence of improved mitochondrial function, sensitivity to insulin, blood sugar levels, blood pressure or activity of DNA repair proteins when supplementing with NR. They did find a reduction in some markers of inflammation.
  • The same study found no evidence of reduced physical frailty, though the study arguably didn’t last long enough to detect such a change.

With this being said, study of NAD boosting in humans is still in its infancy, and we are still in the process of exploring safety and dosing requirements of NAD-boosting molecules. The studies mentioned above are small, short trials with 30 participants or fewer, and we need larger studies before drawing firm conclusions on whether NAD boosting can work in humans.

Senolytics

What is it?

Senolytics are drugs that target and destroy senescent cells, which are ‘zombie cells’ that have ceased to function correctly but refuse to die. Cells become senescent for various reasons, such as when their DNA becomes badly damaged or when their telomeres become too short. Senescent cells lose the ability to divide, which prevents them from becoming cancerous. They are then destroyed by the immune system. Unfortunately, during ageing, senescent cells pile up as they begin to accumulate faster than the body’s immune cells can remove them. Senescence is thought to play a role in most diseases of ageing.

Causes and consequences of cellular senescence.

How does it work?

Senolytics work by activating apoptosis (cell suicide) in senescent cells – a process to which senescent cells are usually resistant. It’s hoped this would help delay the ageing process in a number of ways. Since senescent cells are a ‘dead weight’ that don’t contribute to the operation of a tissue or organ as much as healthy cells, reducing their numbers should improve the function a given tissue. Senescent cells also produce a range of signals that promote inflammation, contribute to the development of diseases of ageing, and can turn nearby cells senescent. Senescence is particularly problematic when it occurs in stem cells, as these are the cells responsible for regenerating damaged tissue. For example, the loss of muscle strength that occurs with age is thought to be due in large part to the senescence of muscle stem cells.

What does the human evidence say?

Like NAD, senolytics have shown promise when it comes to extending lifespan in animal models, but have only recently begun to be tested in humans. Dasatinib (also known as Sprycel) is a drug that blocks cancer growth, while quercetin is a plant flavonol, a group of molecules with potent antioxidant properties. These drugs have been tested in combination (referred to as D+Q) in several human clinical trials:

  • In 14 patients with idiopathic pulmonary fibrosis, D+Q treatment for 3 weeks slightly reduced senescent cell numbers and improved physical functions such as walking speed, though lung function and overall frailty weren’t significantly affected.
  • Another trial looked at D+Q treatment in 11 diabetic subjects with kidney dysfunction. They found significant reductions in senescent cell numbers.

Other senolytics have been studied, but have generally shown less success. The most notable setback for senolytics recently was the failure of a phase 2 clinical trial of a senolytic called UBX0101, which failed to produce significant improvements among 183 patients with knee osteoarthritis. Some argue this trial failed because the drug concentrations tested were too conservative.

Again, we are only beginning to explore the effectiveness of senolytics in humans. There’s still room for cautious optimism when it comes to these drugs, but more research needs to be done.

Targeting mTOR

What is it?

Around 60 years ago, Georges Nógrády was collecting soil samples from different parts of the island of Rapa Nui, also known as Easter Island. He was trying to figure out why the inhabitants, who walked around barefoot, didn’t get tetanus. He handed the samples over to a company that would later be known as Pfizer. What the scientists at Pfizer discovered was rapamycin, a compound produced by a species of bacteria and that had antifungal, antibacterial, anti-cancer, anti-ageing and immune system supressing effects. Researchers eventually worked out that the main target of rapamycin was a molecule called mTOR (mammalian target of rapamycin), which is central to the control of cell growth and division.

How does it work?

Inhibiting mTOR reduces cell growth and division and encourages cells to repair themselves. For example, mTOR inhibition enhances the cellular waste disposal system known as autophagy, allowing cells to better remove damaged proteins and organelles (cellular organs). This includes the removal of damaged mitochondria which, as mentioned previously, are thought to play an important role in the ageing process.

Added drug allows rapamycin to slow aging without risking diabetes –  Science of Singularity
Drugs like rapamycin inhibit mTOR, slowing growth and putting cells into ‘repair and survive mode’.
Source

What does the human evidence say?

Despite rapamycin having a very well established lifespan extending effect in animal models as well as a solid safety profile in humans, there is not much data on whether rapamycin or other mTOR inhibitors can ameliorate or delay age-related diseases in humans, though some clinical trials are under way that should help us answer this question.

  • Even though rapamycin is given to organ transplant recipients to suppress the immune system and prevent rejection, evidence suggests that inhibiting mTOR actually boosts the immune systems of elderly subjects. 264 elderly subjects were given an mTOR inhibitor or placebo for 6 weeks, and those in the treatment group experienced fewer infections, improved flu vaccine responsiveness and increased expression of genes related to defence against viral infection.
  • A small study involving 17 subjects found that rapamycin applied to the skin via a hand cream was associated with increased collagen content, improvements in skin tissue structure, reduced senescence and a younger appearance of the skin after 8 months when compared with those receiving a placebo cream.

Rapamycin is already approved for use in humans, and is one of the most effective drugs for the extension of lifespan in animals. This makes it a promising anti-ageing drug candidate in humans, but we need to see the results of more clinical trials.

Exercise

What is it?

If you’re asking this question, you’re probably not doing enough of it!

How does it work?

Even though we have known about the health benefits of exercise for millennia, how exactly exercise protects us against such a wide range of diseases is poorly understood. Physical fitness seems to protect the body against the negative effects of stress and inflammation. Exercise improves mood and protects against depression, a risk factor in the development of neurodegenerative disease. Muscle strength protects against age-related muscle wasting, while mechanical loading of the bones stimulates bone growth and repair.

What does the human evidence say?

Exercise is one of the better-studied potential anti-ageing interventions on this list. However, evidence concerning the health benefits of exercise is often conflicting because ‘exercise’ can describe a very wide range of activities. What type of exercise is being done, the intensity of the exercise, how long it lasts and how often may all affect the level of benefit gained. That said, research supports many health benefits for exercise, including:

  • Weight loss.
  • Reduced risk of most age-related diseases including heart disease, cancer and neurodegenerative diseases.
  • Improved mood.
  • Improved sleep.

Some studies have tried to discern whether physical activity can affect the biology that is thought to underlie the ageing process:

  • A study with 20 participants found that endurance trained males in their 60s and 70s had longer telomeres on average than similarly aged participants who engaged in medium levels of exercise. For men in their 20s, there was no significant difference in telomere length between those who were endurance trained and those who weren’t. However, as this trial wasn’t randomised, it’s not possible to say whether lower physical activity caused telomeres to shorten faster.
  • One study of 34 males found no significant relationship between cycling experience and telomere length or senescence, but physical activity was associated with reduced inflammation. Again, this study wasn’t randomised.
  • In another trial, 43 males aged 50-72 were randomised to receive an intervention including exercise or no intervention. After 8 weeks, those in the intervention group showed an average 3.23 year reversal in their epigenetic age as measured by DNA methylation, though the intervention also included diet and sleep interventions. However, a later study produced similar findings in female participants who only underwent exercise training.

It’s been nearly 90 years since scientists showed that rats lived longer when their food intake was limited. Unfortunately, we still don’t know whether any interventions exist that can extend the maximum lifespan of humans. If fact, only relatively recently has anti-ageing research in humans begun to be taken seriously, and so our understanding of most of the entries on this list is still in its infancy.

Ageing is a complex problem, and finding an effective anti-ageing treatment isn’t as straightforward as it may seem. An intervention might only be effective when started at a specific stage of life, so a clinical trial might fail because it’s simply looking at the wrong age group. Clinical trials studying ageing tend to include mainly healthy subjects, but the health status of the recipient might affect how effective the treatment is or whether there are side effects. For pharmaceutical treatments, there are also interactions with other drugs to consider. The majority of elderly people take at least one prescription medication, around a third take 5 or more according to estimates.

Though human clinical trials have produced some promising results, we need many more clinical trials to be conducted if we hope to identify interventions with true anti-ageing effects. The advent of machine learning and the identification of improved biomarkers of ageing is likely to accelerate this process, but the road ahead is still likely to be long and bumpy.


References

Clinical Trials Targeting Aging: https://doi.org/10.3389/fragi.2022.820215

Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates: https://doi.org/10.1038/s42003-018-0024-8

Rapamycin fed late in life extends lifespan ingenetically heterogeneous mice: https://doi.org/10.1038/nature08221

Energy restriction and oxidative DNA damage in humans: https://pubmed.ncbi.nlm.nih.gov/7549808/

Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals: https://doi.org/10.1016/j.atherosclerosis.2008.05.036

Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function: https://doi.org/10.1038/oby.2008.201

Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults: https://doi.org/10.1038/s41467-018-03421-7

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts: https://www.nejm.org/doi/10.1056/NEJMoa1800389

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study: https://doi.org/10.1016/j.ebiom.2018.12.052

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease: https://doi.org/10.1016/j.ebiom.2019.08.069

UNITY BIOTECHNOLOGY ANNOUNCES 12-WEEK DATA FROM UBX0101 PHASE 2 CLINICAL STUDY IN PATIENTS WITH PAINFUL OSTEOARTHRITIS OF THE KNEE: https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-announces-12-week-data-ubx0101-phase-2/

TORC1 inhibition enhances immune function and reduces infections in the elderly: https://doi.org/10.1126/scitranslmed.aaq1564

Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial: https://doi.org/10.1007/s11357-019-00113-y

Telomere length and long-term endurance exercise: does exercise training affect biological age? A pilot study: https://doi.org/10.1371/journal.pone.0052769

No effect of the endurance training status on senescence despite reduced inflammation in skeletal muscle of older individuals: https://doi.org/10.1152/ajpendo.00149.2020

Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial: https://doi.org/10.18632/aging.202913

Clinical consequences of polypharmacy in elderly: https://doi.org/10.1517/14740338.2013.827660

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