Anti-aging Benefits of Rapamycin (part 2) - Animal Research

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The drug rapamycin is currently the most effective and reproducible pharmacological approach for directly targeting the aging process to increase life span and health span in laboratory animals (5). Rapamycin positively impacts most hallmarks of aging, and it has been shown to increase life span in each of the major invertebrate model organisms and in rodents (4). Rapamycin increases life span by 10 to 30% in multiple strains of mice when started either early or late in life, and when administered continuously (6, 7), intermittently (8), or transiently (9).

Notably, a single 3-month “high dose” treatment regimen was, in 2016, shown to increase remaining life expectancy of mice by up to 60% over non-treated controls (9). In this study, the total lifespan improvement (14% in males) from the high, 3 month dosing regimen was more than the ITP low dose rapamycin taken from early mouse adulthood through end of life (10% in males), and almost equal to the ITP “moderate dose” regimen from middle age through end of life (20% in males). This suggests that rapamycin may not need to be taken for many decades to still offer significant improvements in health and lifespan.

Not only does rapamycin treatment increase life span but it also delays, or even reverses, nearly every age-related disease or decline in function in which it has been tested in mice, rats, and companion dogs, including cancers, cardiac dysfunction, kidney disease, obesity, cognitive decline, periodontal disease, macular degeneration, muscle loss, stem cell function, spinal disc, and immune senescence.

Rapamycin is what is known as an mTOR inhibitor. mTor is a molecular pathway in organisms that regulates cell growth and proliferation.

Dr. David Sabatini, the MIT professor who discovered mTOR, describes how rapamycin works with mTOR like this:

“Pretend your body is an old house. Your oldest cells have all sorts of problems and are implicated in your house falling apart. You couldn’t fully renovate the old house by bringing in only a plumber, or only an electrician, or a roofer, or a drywall guy, you’d need to hire a general contractor, who would hire all those specialists to come fix all those problems. Rapamycin essentially tricks the body into thinking that it’s in a state of calorie deprivation, which is what causes the general contractor to call in all the guys for renovation work. When that happens, the renovation focuses on your oldest and weakest cell parts, including aging cells.”

Heart Function: Mouse Studies
Mouse studies have shown that if you take a 20-24 month-old mouse (about the equivalent to a 60-65-year-old person), and compare the heart to that of a 6-month-old mouse, you can see declines in heart function just as you can in people.

Rapamycin studies have mostly looked at left ventricular function of the heart (i.e., ejection fraction [EF], fractional shortening [FS], and E/A ratio) via echocardiography.

Three independent studies have shown that 6-10 weeks of rapamycin treatment is enough to cause a reversal of those measures of heart function mentioned above (EF, FS and E/A) in old mice back to about halfway to that of the young mice (that is, it takes a 60-65-year-old back to about a 30-year-old in a human equivalent approximation)

Dental Rejuvenation: Mouse Studies
In another study out of Matt Kaeberlein’s group, it was shown that rapamycin can regenerate bone and decrease gum inflammation, pointing the way toward new treatments for common dental problems in aging patients.

In their studies of rapamycin in old mice, the researchers found another intriguing effect: The drug significantly changed the oral microbiome, which is the mouth’s bacterial population. They discovered that old animals not only had a different oral microbiome than the young animals, but that rapamycin treatment reversed changes in the old oral microbiome, making it more similar to what was found in younger animals. See the full story and interview on this study here: New Study: Rapamycin Rejuvenates Oral Health in Aging Mice

Blood Stem Cells
When the researchers treated mice with rapamycin, beginning at a young age, they were able to prevent blood stem cells from enlarging (a key sign of age for stem cells) as the mice got older. Blood stem cells from those mice remained small and were able to build blood cells like young stem cells even in mice 3 years of age — an old age for a mouse.
Source: Rapamycin Prevents Blood Stem Cell Aging, New MIT Study

Weight and Obesity Prevention: Mouse Studies
Two studies have shown that rapamycin can prevent obesity in mice fed high fat diets.
Matt Kaeberlein stated in a recent twitter post: “we show in this paper that rapamycin prevents diet induced obesity in mice and activates CEBP/b target genes”.

Reduction of Visceral Fat: In unpublished data, it has been stated that the reason PEARL trial chose visceral fat loss as the primary endpoint is because one of its collaborates Dr Watson had previously done a very small Rapamycin trial and the biggest effect he saw was a reduction of visceral fat on DEXA scan.

Rapamycin may delay or reverse reproductive aging in females
There are already several lines of evidence in mice that rapamycin delays (reverses?) reproductive aging in females. Here is one such study: Short‐term rapamycin treatment increases ovarian lifespan in young and middle‐aged female mice. Related to this, in a recent study rapamycin prevents structural birth defects in fetuses of mothers with diabetes. News report here, research paper here.

Heart Function: Dog Studies
Matt Kaeberlein group at the University of Washington did a 10-week study of rapamycin in middle-aged healthy companion dogs looking at heart function as their short-term measure. Just as in the mouse studies, he study saw improvements in heart function in the treated dogs. The dogs that got the biggest benefit with rapamycin are the ones that started with the lowest hear function.

Interestingly, out of that study came a case study of a Doberman and cardiac function. Dobermans as a breed are highly prone (60-65%) to dilated cardiomyopathy. In the study, one owner of a Doberman in the study was giving her dog echocardiograms before coming into the study. That Doberman happened to be randomized into the higher rapamycin group and had one of the best responses in terms of improved cardiac function. The Doberman went from borderline dilated cardiomyopathy to ~10% improvement in EF, which is well into the normal range.

Rapamycin in cancer treatment
Immune surveillance is one of the most important anti-cancer mechanisms, Matt Kaeberlein has suggested. And we know that immune function goes down with age. If you can boost age-related immune function with rapamycin, enhance immune surveillance, that’s going to have a potent anti-cancer mechanism. This might be why we’re seeing—in the studies in mice—that cancers are pushed back during aging by rapamycin. But if the rapamycin dose is too high, and it’s inhibiting immune function, it might be detrimental.
Sample of rapamycin/cancer research:

Matt Kaeberlein’s study on mice giving them the ‘Hi-dose’ (8 ml/kg/day injections) of rapamycin had very different effects between male mice and female mice in this study. Male mice lived 60% longer after the end of treatment, with better muscle function, and less cancer. The Female mice had no difference in lifespan, but they died with very different types of cancers (all had aggressive hematopoietic cancers compared to 30-40% in the rapamycin-treated [not uncommon for these mice to get this cancer]). Matt Kaeberlein believes that rapamycin does more than just reducing the rate of deterioration and decline in aging

Rapamycin in Marmoset Monkeys
Numerous safety studies have been conducted on healthy marmosets, which suggests rapamycin is safe and will work well in healthy human populations.

A longterm study published in 2015 found: Rapamycin treated subjects showed no overall changes in daily activity counts, blood lipids, or significant changes in glucose metabolism including oral glucose tolerance. Adipose tissue displayed no differences in gene expression of metabolic markers following treatment. Overall, the marmosets revealed only minor metabolic consequences of chronic treatment with rapamycin and this adds to the growing body of literature that suggests that chronic and/or intermittent rapamycin treatment results in improved health span and metabolic functioning. In summary, the study found no notable metabolic problems in a group of the monkeys who received rapamycin in human-equivalent doses for a year, and they lost significant amounts of body fat in the early months.

In another long term study, 2019 Sills et al. evaluated the safety of rapamycin on 23 middle-aged marmosets who were fed rapamycin for nine months. The marmoset showed no significant side effects and only minor effects on hematological markers. Since marmosets are biologically similar to humans, the study suggest similar outcomes would occur in humans.

Relevant Rapamycin Studies

Rapamycin study in marmosets : Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus) (Ross et al., 2015)

Story including the dog aging project and long-term goal of five-year study : The puzzle of aging: UW experts are piecing together new ways to live longer and better | The University of Washington Alumni Magazine (magazine.washington.edu)

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https://elifesciences.org/articles/62233

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Rapamycin changes the way our DNA is stored

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