Fight Aging!

This popular science piece covers some of the major themes of recent years in the development of calorie restriction mimetic drugs, pharmaceuticals intended to recreate at least a little of the beneficial metabolic response to lowered calorie intake. The article is a cut above the average in terms of quality, but I remain bothered that this line of work receives so much attention in comparison to far better approaches to the treatment of aging, such as the SENS portfolio of therapies based on repair of the molecular damage that causes aging.

Calorie restriction mimetics cannot produce rejuvenation, and cannot do more than slightly slow aging. They are enormously challenging and expensive to develop, as illustrated by the past fifteen years of investment and failure: there is still no viable, reliable, useful choice if you want to take a calorie restriction mimetic drug, and there is still no full accounting of the cellular biochemistry of the calorie restriction response. The drug candidates on the table such as metformin, mTOR inhibitors, and autophagy enhancers are all some combination of only marginally effective, possessed of unreliable data from animal studies, or producing undesirable side-effects. None come close to the reliability and benefits of calorie restriction itself, but even that buys little in humans, considered in context of the bigger picture of what is possible via the SENS approach of damage repair. People taking a hypothetical perfect calorie restriction mimetic would still age and die on much the same schedule as their untreated peers, gaining only modest benefits. We can do better than this.

Soon to be 50, the respected head of an Australian medical institute is contemplating the latest offering from the anti-ageing industry. It's a product that tops up the levels of nicotinamide adenine dinucleotide (NAD+), a commonplace chemical made by our bodies that is crucial for our metabolism. He's not alone. Leonard Guarente has been taking NAD+ boosters for years; and in 2015 started a company, Elysium, to market them. There are likely thousands of users by now. Something has changed in the anti-ageing field. Eccentrics and gullible-types have always availed themselves of anti-ageing remedies. Dubious supplements feed a mushrooming $30 billion industry. But when evidence-clamouring scientists start popping a pill, you sit up and take notice. Like the soon-to-be-50 Australian professor, most aren't aiming to extend their lifespan; they are aiming to extend their "health span" - the period of time before the diseases of ageing catch up with them.

The rough rule of thumb in nematode worms is: restrict calorie intake by 30% and see up to a 30% increase in lifespan. The effects are smaller in mice and even smaller in primates. Not many people have the willpower to adhere to a lifelong diet, though occasional "fasting mimicking diets" seem to have beneficial effects. Nevertheless the holy grail has been to find a drug that could mimic fasting. Calorie restriction flips a metabolic switch from "abundance" to "austerity". Like when you get a big salary cut, you don't go adding extensions to the house; you hunker down, live modestly, recycle your old things and delay your plans to have babies. Somehow responding to this stress also lengthens lifespan. These days researchers think autophagy plays a big part in the lengthening. For instance, recent studies on mice and humans shows that fasting accelerates the refurbishing of tissues, clearing away damaged "senescent cells" while turning on renewing stem cells.

You might think with all the epiphanies of the past 30 years, surely we know enough about ageing to go full speed ahead with interventions? All the candidate compounds, so far, seem to hack into the same pathway triggered by calorie restriction. Well, yes - but this rabbit hole goes very deep. Over the years, one compelling theory has been that it controls the integrity of mitochondria, the engines of our cells which clearly degenerate as we age. According to the theory, the corrosive by-products of cellular combustion - free radicals - cause ongoing damage as an inevitable consequence of being alive. But numerous recent experiments show that slowing the generation of free radicals in mice or flies doesn't actually slow the ageing process. In fact, it seems to have the opposite effect. Nowadays the paradigm shift is that stress signals like those from free radicals, fasting, or exercise trigger an adaptive anti-ageing response. It doesn't mean past theories are entirely wrong. It's just that there is a lot of other stuff going on in ageing as well.

None of this means the era of anti-ageing medicine has to wait for us to explore every blind alley of the rabbit hole. Indeed, most of the researchers I spoke with passionately believe they are more than ready to start testing the plethora of promising new compounds in their pipelines. What's needed is the faucet at the end - the regulatory framework that will incorporate "ageing" as a medical indication.

Link: https://cosmosmagazine.com/biology/time-to-pop-an-anti-ageing-pill