Background
When researching growth and development in the 1930s, US biochemist Clive McCay discovered to his surprise that his laboratory rats lived longer when he fed them less[82]. These rats were not starved. McCay made sure they got all the nutrients (including vitamins and minerals) they needed. The only thing the rats had too little of was calories. This type of diet has since been dubbed calorie restriction and has become a cornerstone of life extension research.
Since Clive McCay’s discovery, calorie restriction has been heavily researched as an anti-aging approach. Several scientists have found results similar to McCay in yeast,[83]worms,[84]and mice.[85] There have even been two large-scale studies of the phenomenon in one of our close relatives, the rhesus macaque. These studies have taken decades because monkeys live relatively long lives. One showed the expected result, one did not.[86]
It would seem likely that caloric restriction strategies can be effective in humans, but the matter is not as simple as it seems, and other health aspects need to be taken into account as well.[245] Much of the research into calorie restriction has been basic research to learn more about what drives the aging process. Even though there actually is an organization for proponents of calorie restriction called the Calorie Restriction Society, most people would not take up the lifestyle even if it proved beneficial. For this reason, scientists are focused on understanding how calorie restriction works in order to derive easier ways of achieving the same benefits. If we can understand the biochemical pathways involved in the response, we can develop drugs that mimic this effect. This idea is similar to the idea of “exercise in a pill” that is sometimes floated. Using a calorie restriction mimetic, your body would react as if you were undergoing calorie restriction, but without the physical discomfort of being tired, hungry, and cold for the rest of your life.
Some scientists suspect that constant calorie restriction is not actually necessary, and that occasional fasting will provide the same benefits with less discomfort. For instance, in a mouse study, the mice that were subjected to daily fasts (but received sufficient calories) lived just as long as the calorie-restricted mice.[87] Meanwhile, mice that have unrestricted access to very low-calorie feed do not live longer.[88] These mice end up being calorie restricted but are constantly eating, suggesting the fasting response could be more important for life extensions than calorie intake.
Hormesis
The connection between energy intake, metabolism, and aging has been known for a long time, but is still not fully understood, with several different theories having been proposed.
Some scholars believe the connection between the three factors is mainly based on the phenomenon of hormesis, in which a little bit of a bad thing becomes a good thing. This is because a challenge ramps up our defenses and makes us stronger. Exercise is the best example. Think about what happens on a run: your muscles are working overtime, your bones are put under stress, your heart is pumping fast, and your lungs are struggling to provide enough oxygen. Right after you finish you're weaker than before. But give your body a little time to relax and it will adapt. Your muscles, bones, heart, circulation, and lungs all become stronger. The “damaging” exercise turned out to be a good thing. It will even help you live longer.[89] The same might be true for calorie restriction and fasting. By putting stress on the cells, protective measures such as repair and recycling might be boosted.
IGF1
Another potential mechanism involved in calorie restriction and fasting revolves around growth pathways. It all starts with the growth hormone (GH). This hormone is produced in the pituitary gland and travels to the liver, where it promotes production of another hormone called insulin-like growth factor-1 (IGF-1). It is IGF-1 that is actually responsible for most of the effects of GH.
If the body has sufficient GH, but lacks IGF-1, the result is a kind of dwarfism called Laron Syndrome.[90] This genetic condition occurs with a low incidence around the world. It is especially common in the remote mountains of Ecuador. Scientists have studied Laron Syndrome patients from this region and found that they have remarkably low rates of cancer and other age-related diseases.[91] Mice with the same disorder also end up being very small and very healthy. They have some of the longest lives of any mice.[92]
All of this is relevant because calorie restriction predictably decreases serum IGF-1 levels in mice.[93] Thus, we know that mice with very low natural IGF-1 levels live longer, that IGF-1 levels can be decreased in normal mice by calorie-restricting them, and that these mice then go on to live longer.
We do not know exactly why IGF-1 is conducive to higher life expectancy. As the name implies, it promotes growth of different tissues. However, it is not necessarily growth itself that causes us to age. In a study in worms, scientists found that the aging effects of IGF-1 could be isolated to the nervous system. In muscle tissue, the hormone turned out to be beneficial.[94] Growing muscle does not contribute to aging.
However, growth could be part of the answer. We know that in the animal kingdom, smaller members of a species live longer than larger ones. While dogs are bigger than mice and live longer, within both dog and mouse populations, smaller individuals live longer. The same appears to apply to humans. When we compare the statures of some of the longest-lived people, it is notable that most have been very short and none of them very tall. Jeanne Calment, who is considered the longest-lived person to date (though that claim is controversial and contested), was 150 cm (4’11) tall, while the runner-up, Sarah Knauss, was 140 cm (4’7). If you are tall, there is no reason to despair, though. Current generations are taller than ever, but also have a longer life expectancy than earlier ones. Moreover, the effect is not very pronounced. Many tall people live longer than many small people.
Another mechanism involved might be the similarity between IGF-1 and the hormone insulin. In organisms such as yeast, a single hormone fulfills the role of both of these. This is not the case in humans, but the similarity is big enough that IGF-1 and insulin can activate each other’s receptors.[95]
After we eat, most of the carbohydrates in our meal eventually end up as glucose in the blood. Our pancreas produces insulin to tell the cells to take up the glucose and use it as fuel (or alternatively, the fat cells convert it to fat).[96] This mechanism is dysfunctional in Type-2 diabetes, which has become a major health issue worldwide. Here, the cells do not respond to the insulin, even though production is ramped up. This condition is associated with shorter lifespans.[97]
mTOR and rapamycin
In the 1960s, scientists went to Rapa Nui (Easter Island) in the Pacific to explore its soil microbes. They found a bacterium called Streomyces hydroscopicus that produces a special compound to protect itself against fungi. The compound is one of the bacterial answers to the many antibacterial compounds produced by fungi. Famously, antibiotics (the compounds used to kill bacterial infections) were first discovered in fungi. In the never-ending turf war between microbes, bacteria-killing compounds can give fungi an upper hand; the compound discovered on Rapa Nui is an example of how one bacterium fights back.
The fungi-killing compound was named rapamycin, after its place of discovery. Its effect on fungi is due to inhibition of a special enzyme called target of rapamycin (TOR). This critical protein is the central growth regulator of the cell and is so important that it has been conserved by evolution throughout hundreds of millions of years. Our own closely related version, called mTOR (mammalian target of rapamycin), is also inhibited by rapamycin.
As a weapon against fungi, it is highly sophisticated. Targeting the main growth regulator makes sure that even low concentrations help inhibit the enemy. And high concentrations are obviously lethal. But despite the intended purpose as a deadly weapon, rapamycin has found an unlikely role as the most promising anti-aging drug right now. Ironically, at the right concentrations, it can even be used to extend the life of yeast (a type of fungus).[98] It also works in flies,[99]worms,[100] and most importantly, mice.[101]
It is already approved for use in humans because it has historically been used to suppress the immune system in transplant patients. However, these patients are obviously not the best subjects for studying life extension. There have been small safety trials in healthy humans with positive results,[102] but it is not yet known whether rapamycin could have the same positive effects on humans as in laboratory animals.
All of this ties together because mTOR is situated downstream from growth hormone, IGF-1, and insulin. They all participate in the same pathways with mTOR eventually being activated by the others.
Sirtuins
Proteins called sirtuins work in the opposite direction of mTOR and the growth hormones. They signal that there is a scarcity of nutrients. This makes them obvious candidates for calorie restriction mimetics. Their overexpression seems to be able to extend the lifespan of several model organisms,[103] but this is a controversial issue. Sirtuins works by detecting high levels of the molecule nicotinamide adenine dinucleotide (NAD+).[104] For this reason, there is a lot of interest in using supplements to raise the level of NAD+. By mimicking a low-energy state, these supplements could be the calorie restriction mimetic we are looking for.
Challenges
We still have not deciphered the entirety of the interplay between nutrients, metabolism, growth, and longevity. mTOR is one of the most promising targets. However, mTOR actually exists in two different protein complexes in our bodies: mTORC1 and mTORC2. It is mTORC1 inhibition that seems to drive the benefits, while mTORC2 inhibition is responsible for most of the drawbacks.[105] Much as in the case of IGF-1, which is only conducive to aging in some tissues, this is an example of the complexity of cellular signaling. We will need a deeper local understanding to advance treatments with a low risk of side-effects. Furthermore, while interventions in this field tend to work very well in smaller organisms, the effects are progressively diminished the closer we get to humans.
Road to Success
There are a lot of different ways to target this hallmark of aging. That actually makes it harder to achieve success. The pathways connecting nutrients, metabolism, growth, and lifespan are heavily researched, but research in this area is also fraught with controversies. The jumble of proposed mechanisms and interactions makes it hard to be certain of causes and effects.
In principle, this is a perfect area of activity for the pharmaceutical industry; many of the effects could probably be unlocked by simple inhibition of certain enzymes or the boosting of others. The challenge is avoiding side-effects, and although this is a well-known issue across all areas of pharmacology, the risk-benefit equation is different when it comes to preventive anti-aging drug treatments than when developing drugs to treat severe diseases.
Companies
L-Nutra[106]
Website http://www.l-nutra.com
Industry Health, Wellness & Fitness
Company size 51-200 employees
Headquarters Los Angeles, California
Type Privately Held
Founded 2009
L-Nutra was founded by cell biologist Valter Longo from the University of California. A prominent expert on fasting and nutrient response in aging, Longo also conducts research on how to transfer the results from model organisms to humans. The result of his work is the fasting mimicking diet, which aims to deliver the benefits of a long fast without the inconveniences. L-Nutra has developed a five-day diet based on this approach called Prolon. It is plant-based and contain meals designed to inhibit the same metabolic pathways as fasting.
Rejuvenate Bio[107]
Website http://rejuvenatebio.com
Industry Biotechnology
Company size 2-10 employees
Rejuvenate Bio was founded by a group of biologists including synthetic biology pioneer George Church. The company is developing a gene therapy for aging that will first be tried in dogs. The gene therapy consists of FGF21, sTGF2betaR, and alpha-Klotho. All of these have been identified as anti-aging hormones that play a role in the pathways connecting metabolism and longevity. FGF21 is induced by fasting, for instance.[108] The company's lead compound RJx-01 is a combination product indicated to tread Sarcopenia- the progressive loss of skeletal muscle quality and mass as well as physical strength. It affects between 2 and 24 percent of the overall population, and 50 percent of all 80-year-olds. It increases the risk of physical disability, poor quality of life, and death.
Mount Tam Biotechnologies
Website http://www.mounttambiotech.com
Phone +1 4252144079
Industry Biotechnology
Company size 11-50 employees
Headquarters Novato, California
Type Public Company
Founded 2014
Mount Tam Biotechnologies focuses on discovering and developing new modulators of mTOR, also called rapalogs. These can be used to treat a range of conditions such as autoimmune diseases, by inhibiting the immune system, and cancer, by inhibiting growth.[109] At a later stage, the knowledge and new pharmaceuticals developed in this context can also be tested in anti-aging interventions.
Navitor Pharmaceuticals[110]
Website http://www.navitorpharma.com
Industry Biotechnology
Company size 11-50 employees
Headquarters Cambridge, MA
Type Privately Held
Founded 2010
Navitor Pharmaceuticals develops selective mTORC1 inhibitors. Research has shown that the potential life extension benefits of inhibiting mTOR are attributable to mTORC1 inhibition, while many of the side-effects are due to mTORC2 inhibition. By creating selective mTORC1 inhibitors, Navitor Pharmaceuticals hopes to develop an anti-aging drug without serious side-effects. Currently, the company is conducting a phase 1 clinical trial for the brain mTORC1 activator NV-51-38 (implicated in depression) and is preparing for a phase 1 clinical trial of its mTORC1 inhibitor NV-20494.
resTORbio[111]
Website https://www.restorbio.com/
Industry Biotechnology
Company size 2-10 employees
Headquarters Boston, Massachusetts
Type Public Company
Founded 2016
resTORbio develops selective mTORC1 inhibitors. Research shows the potential life extension benefits of inhibiting mTOR stem from mTORC1 inhibition, while many of the side-effects are from mTORC2 inhibition. By creating selective mTORC1 inhibitors, resTORbio hopes to develop an anti-aging drug without serious side-effects. The company is currently conducting several clinical trials. In November 2019, the company announced that a Phase 3 trial of its lead product candidate, an oral mTORC1 inhibitor called RTB101, has failed to reduce the incidence of respiratory tract infections in patients aged 65 and above.[210] RTB101 continues to be trialed against Parkinson’s Disease in combination with rapamycin. If the trial is successful, the company aims to develop RTB101 for other aging-related diseases.
Chromadex Corp[112]
Website http://www.chromadex.com
Industry Health, Wellness & Fitness
Company size 51-200 employees
Headquarters Los Angeles, California
Type Public Company
Founded 1999
ChromaDex is a nutraceutical company. As the holder of multiple patents, it is the sole manufacturer of commercially available nicotinamide riboside. This supplement is used to raise intracellular levels of the anti-aging molecule NAD+.
Elysium Health[113]
Website http://www.elysiumhealth.com
Industry Biotechnology
Company size 11-50 employees
Headquarters New York, NY
Type Privately Held
Founded 2014
Multiple prominent experts are involved in Elysium Health, an anti-aging company that sells the supplement “Basis” developed by Leonard Guarente. This supplement is purported to increase NAD+ levels, which activates sirtuins. It also offers test of epigenetic age and sells a supplement called “Matter”.
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