Posted on 4 March 2021
Scientists once believed that ageing was a complex process that was impossible to cure. Many thought that ageing was a consequence of a combination of processes, and would therefore not be slowed down by any single treatment. However, numerous animal models have demonstrated that the ageing process is malleable.
Various drugs, calorie restriction, and mutations in single genes can all significantly extend lifespans or slow aspects of the ageing process in animals, ranging from the worm C. elegans to primates. The challenge in demonstrating longevity extension in people is greater, but there is no reason to believe interventions that can extend human lifespan do not exist.
In order to bring us closer to the goal of extending the lifespan of humans, the National Institute on Aging (NIA) set up the Interventions Testing Program (ITP), a program designed to test the ability of compounds approved for human use to prolong lifespan in mice.
The purpose of the ITP is to test drugs that are capable of extending mouse lifespan in a rigorous way. It is considered by many to be the gold standard for this purpose due to the following experimental practices:
Furthermore, the ITP focuses on testing compounds that have already been approved in humans for the treatment of other diseases, and therefore have a robust safety profile, lowering the barrier for conducting clinical trials in humans.
All results from the ITP studies to date are available for viewing (they are summarised in the table below). Here’s a listing of the interventions that have had the most success in the ITP so far. All of these interventions resulted in statistically significant (P<0.05) increases in median lifespan for both male and female mice.
A word on median and maximum lifespan:
Median lifespan refers to the life expectancy of a mouse that outlives half of its peers and is outlived by the other half. Although it is similar to the mean (aka average), it is less affected by outliers: a mouse that dies minutes after birth will not significantly affect the median.
Maximum lifespan is the age of death of the longest-lived mouse. However, a far more useful metric that is similar to maximum lifespan is P90 lifespan extension. The P90 lifespan is the age at which 90% of mice are deceased. From now on when we mention an increase in maximum lifespan, we are actually referring to an increase in the P90 lifespan.
Rapamycin is an immune suppressant drug used to help prevent the rejection of organ transplants. It works by reducing the sensitivity of white blood cells (specifically T and B lymphocytes) to activating signals. It does this by inhibiting a protein called mTOR, which also happens to be an essential regulator of the cell’s response to the availability of nutrients. This ‘nutrient sensing pathway’ is thought to play a key role in the ageing process, and is one of the ways in which caloric restriction is thought to work to extend lifespan.
In the ITP, rapamycin has shown significant extension of median and maximum lifespan in both males and females in multiple studies. In one of these studies, when given at 20 months of age, rapamycin was associated with a 20% median lifespan increase in males and a 13% increase in females, though this sex difference is reversed in some other ITP studies, and overall the effects of rapamycin on males and females is thought to be similar. The fact that these mice were 20 months old is noteworthy, as they are considered ‘equivalent’ to 60 year old humans. This hints that mTOR inhibition may be able to extend lifespan even when initiated in older age. Comparatively, calorie restriction typically does not work when started at this age.
Acarbose is a drug used to treat type II diabetes mellitus. It works by inhibiting enzymes in the gut that are necessary to break down carbohydrates.
The initial ITP study of acarbose found that it was able to extend median lifespan by 22% in males and 5% in females when given at 4 months of age, while also extending maximum lifespan, though this wasn’t always the case for females. However, a repeat study found that Acarbose was only half as effective in males when given at 16 months of age, and had no significant effect on the median female lifespan.
17α-estradiol is a weak oestrogen, with a potency around 100 times lower than that of the main oestrogen 17β-estradiol. 17α-estradiol only extends lifespan in male mice, and appears to work by altering aspects of the metabolism and reducing age-related inflammation. Most benefits of 17α-estradiol are reduced or inhibited in castrated mice, suggesting that it’s effects are at least partly the result of reduced effects of testicular hormones.
Initial ITP studies showed a 12-19% median lifespan extension in male mice when treatment began at 10 months, and also extended maximum lifespan by 12% at sufficiently high doses. Their latest findings, now in the late stages of revision, suggests that 17α-estradiol is equally effective when given at 16 months.
NDGA is an antioxidant compound found in the creosote bush. Antioxidants are molecules that can neutralise reactive oxygen species (ROS). These are unstable molecules can that ‘steal’ electrons from proteins, causing them to become damaged. ROS are thought to be an important driver of the ageing process, as they can damage both your DNA and the DNA inside your mitochondria, the ‘power plants’ that provide the cell with energy.
Unfortunately, the ITP has only found benefits for NDGA in male mice, ranging from 7% to 12% median lifespan increase across 4 studies. The sex difference may have been due to differences in drug metabolism.
Glycine is the smallest and most simple of the amino acid building blocks used to construct proteins. It thought to extend lifespan by mitigating the toxicity of another amino acid, methionine. Glycine is the only drug tested by the ITP besides rapamycin to show similar benefits in both females and males, though these benefits are slight: around 5% increased median lifespan.
Canagliflozin is a member of a class of drugs called SGLT2 inhibitors. These drugs have been around for some time, and are used to treat type II diabetes. They work by blocking the reuptake of glucose by cells in the kidneys, causing more glucose to be excreted in the urine.
An ITP study has shown that canagliflozin can increase median lifespan in male mice by 14%, and increased maximum lifespan by 9%, but has no benefit for females. The simplest explanation for the observed benefit is that it is the result of a reduced blood sugar, however, evidence suggests that the inhibition of SGLT2 actually has health benefits that are independent of low blood sugar. It is also not clear why females did not benefit from the intervention in this case. One hypothesis is that the ageing process in males is more sensitive to glucose. This could also explain why acarbose is less effective in females than in males.
Besides the effectiveness of individual treatments, there are a few general lessons that we can learn about lifespan extension in mice.
These lessons should help to steer medical research in the right direction to eventually forge a path to human lifespan extension.
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice: https://dx.doi.org/10.1038%2Fnature08221
Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males: https://dx.doi.org/10.1111%2Facel.12170
Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice: https://dx.doi.org/10.1111%2Facel.12786
Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer: https://dx.doi.org/10.1111%2Facel.12496
Glycine supplementation extends lifespan of male and female mice: https://dx.doi.org/10.1111%2Facel.12953
Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice: https://dx.doi.org/10.1111%2Fj.1474-9726.2008.00414.x
Canagliflozin extends life span in genetically heterogeneous male but not female mice: https://doi.org/10.1172/jci.insight.140019
SGLT2i: beyond the glucose-lowering effect: https://doi.org/10.1186/s12933-020-01071-y
Peter Attia: #148 – Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program: https://peterattiamd.com/richardmiller/