In terms of proving major ecological truths, the Biosphere 2 experiments were a failure. As an illustration of what can happen when somewhat marginal science meets extreme wealth, they were fascinating. There were intense arguments on both sides of the glass. In 1994, Ed Bass, an oil dynast who had paid for the facility, threw out the management team and put Steve Bannon, later a key adviser to Donald Trump, in charge. At the same time, however, there was what some considered a breakthrough in the science of human aging.
One of the eight biospherians was Roy Walford, professor of pathology at the University of California, Los Angeles (UCLA). Research by Walford and others had shown that limiting what animals ate could significantly extend their lives. The lifespans of nematode worms, fruit flies, rodents and dogs could be extended by as much as 50% by laboratory protocols that fed them a diet with all the nutrients they needed in terms of minerals, vitamins and the like, but fewer calories than thought. normal.
Biosphere 2 allowed him to test the theory on people who were not in a position to go out for snacks. With a daily intake of 1,750-2,100 calories (7,320-8,790 kilojoules), the Biospherians, who were slim to begin with, have all slimmed down. But after eight months their weight stabilized. No matter how thin they were, their energy levels remained high. Blood tests showed physiological responses that matched those of longer-lived, calorie-restricted rodents.
Some people have seen this as a reason to incorporate calorie restriction into their lives, as Walford did. But such diets, which go far beyond the kind of weight-control efforts any reasonable person might aspire to, are difficult to maintain. That has sparked an interest in finding ways to reap the benefits of calorie restriction without having to participate in it.
The garden of forking paths
Calories are a measure of the amount of energy cells can get by breaking down food into its chemical components. The precise nature of that breakdown, and what happens to all the parts, is controlled by a series of signaling pathways whose job is to match what the cell does with the amount of energy the organism needs and has available. Dysfunction in these nutrient signaling pathways is one of the twelve hallmarks of aging that Dr. López-Otín and his colleagues list.
If there is a general truth behind the success of calorie restriction, it is that when energy is in short supply, the nutrient signaling pathways in the cells pay more attention to what is going on and keep the cell in better condition. What is needed if the same routes are to be used without the calorie reduction is an understanding of which other signals can have the same effect.
The research would be both easier to conduct and easier to understand if these pathways all had different, clearly understood functions. Unfortunately this is not the case. Pathways often regulate more than one function, functions are often regulated by more than one pathway, and the most remote parts of pathways are often obscure. To make matters even less understandable, the proteins involved in the pathways have incredibly obscure names.
Take the MTORC1 trail. The complex of proteins that gives it its name first came to attention because an immune suppressant called rapamycin has a strong effect on it: hence "mechanistic target of rapamycin complex 1". However, that provides no real clue to the fact that the signaling pathway that MTORC1 is involved in is a complex series of controls and feedbacks designed to regulate metabolism in response to both nutrient availability (e.g. glucose, which provides energy, and amino acids, from which proteins are made) as well as barriers to their use (e.g. low oxygen levels).
The scope of this regulatory power is broad; it affects the rate at which cells break down damaged internal structures ("autophagy"), the balance of their protein content ("proteostasis") and the reproduction of their mitochondria, components responsible for converting the calories they receive into a form of energy. can use proteins. Autophagy, proteostasis and mitochondrial reproduction are three more of the twelve hallmarks of aging.
Rap of the ages
Moreover, rapamycin, whose action MTORC1 owes its name, appears to extend the lives of laboratory animals, even though it inhibits their immune responses. This has led some longevity enthusiasts to seek off-label recipes for it. But its side effects, including anemia and insensitivity to insulin, make rapamycin unsuitable for widespread use. So the search is on for 'rapalogs' that offer the benefits of a coordinated MTORC1 trajectory without too many costs.
Another pathway that calorie restriction studies have identified as promising is named after a protein called AMPK (don't ask). This regulates the production of ATP, a small energy-carrying molecule produced in the mitochondria. When ATP levels drop, the AMPK pathway increases a cell's sensitivity to insulin.
Metformin, a drug used to treat type 2 diabetes, does this by activating the AMPK pathway. Like rapamycin, it extends the lifespan of healthy mice. The same goes for people with diabetes. A study published in 2014 found that diabetes patients treated with metformin had a lower mortality rate, compared not only to patients not treated with it, but also to healthy controls who did not receive the drug.
Not surprisingly, metformin is also used off-label, probably more widely than rapamycin. The nonprofit American Federation for Aging Research hopes to soon launch a six-year, 3,000-person clinical trial to measure its effects in people ages 65 to 79. The Targeting Aging with Metformin (TAME) study will determine whether metformin helps prevent cardiovascular disease, cancer and cognitive decline; it will also test the hypothesis that it reduces mortality from all causes.
Another set of drugs developed to treat diabetes but now in more widespread use are the GLP-1 receptor agonists. The best known, semaglutide (sold as Wegovy), has been specifically registered in several places for use in people without diabetes who still need to lose weight. Whether they live longer than someone with the same final weight who does not use any of the drugs is an open question. There are no published studies showing that the drugs have an effect on the lifespan of laboratory animals.
One thing that does work well in laboratory animals is taurine, an amino acid that is often used as a nutritional supplement. According to a recent paper by Parminder Singh of the Buck Institute for Research on Aging in Novato, California, and colleagues, taurine increases lifespan in mice by 10%; some of this appears to be due to nutrient signaling. But there are also effects on four or five other hallmarks of aging. Taurine levels decrease with age in people, but in people who live over 100 years, levels remain significantly higher.
Nutrient sensitivity can also be enhanced by a molecule called NAD+. Some enzymes - proteins that catalyze chemical reactions - need the presence of a small extra molecule to do their thing. NAD+ is such a 'coenzyme'. More than 300 enzymes are needed to contribute to the cell. And if you give mice more of it, they live longer.
Given that NAD+ is so generous with its benefits, it's difficult to know exactly which of the enzymes it helps are responsible for delivering this effect. But one connection that seems particularly interesting is with a set of proteins called sirtuins.
La vie en vin rouge
Sirtuins came to prominence 20 years ago when David Sinclair, now co-director of the Center for Biology of Aging Research at Harvard University, showed that boosting its production extends the lives of a variety of laboratory animals. One form of stimulation is calorie restriction. But Dr. Sinclair discovered a chemical alternative: resveratrol, a molecule found in the skin of red grapes, among other things.
Dr. Sinclair is by no means publicity shy; his discovery caused a lot of fuss. He founded a company, Sirtris, which produces resveratrol derivatives suitable for the human body. The work wasn't much. Sirtris, purchased by GlaxoSmithKline, ceased to exist as a separate entity in 2013.
That may seem like a cautionary tale. But it can also be seen as a reason for hope. Sirtuins received a lot of attention because there had been no similarly credible longevity claims for some time. Their story provided a blueprint for investigating such things: a mechanism looked interesting, a molecule seemed promising, research was done, conclusions were drawn. Many more mechanisms and drugs are now being investigated in the same way. Some skepticism is justified. But there's no reason to believe that none of these will yield results just because the few that have been studied so far haven't.
© 2023, The Economist Newspaper Limited. All rights reserved. From The Economist, published under license. Original content can be found at www.economist.com
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Updated: Nov 25, 2023 2:30 PM IST
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