Old Age May Be Too Late For Some Anti-Aging Treatments

5 December 2020
Christopher C. Smith
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New research is likely to provoke a greater sense of urgency among life extension enthusiasts. The research is related to a drug that facilitates cellular processing of glucose in type-2 diabetes patients with insulin resistance. The drug is Metformin.

Metformin works by inhibiting cellular respiration. Cellular respiration is like breathing. Mitochondrial cells “breathe” in the sense of taking up oxygen from the blood, using it to produce energy, and then releasing carbon dioxide into the blood as a waste product.

Recently, scientists have shown that metformin also extends lifespan in animal models. Diabetes patients treated with the drug tend to enjoy longer lives as well. But it’s unclear whether that’s just because it helps with their disease, or whether they might be benefiting from a more general anti-aging property of the drug.

Might the drug be able to extend the lives of non-diabetic patients? Clinical trials are now under way to answer that question.

But there’s a caveat after close examination of the animal studies. The studies that show an anti-aging benefit from metformin focused on animals treated with the drug from young adulthood, whereas studies in older animals found either no benefit or a harmful toxicity.

This observation led a team of researchers from Germany to more closely examine whether metformin affects cells differently depending on their stage of life. In a paper published last month in Nature Metabolism, the German team studied metformin’s effects in different age cohorts of roundworms and human cell cultures.

The topline finding from the paper is that “metformin shortens lifespan when provided in late life, contrary to its positive effects in young organisms.” In elderly organisms “it exacerbates ageing-associated mitochondrial dysfunction, causing respiratory failure.”

More specifically, the researchers divided their roundworms into 10 age cohorts, and their metformin treatment into three dosage levels.

In the four youngest cohorts, all three dosage levels increased the animals’ median and maximal lifespan. In the eighth (middle-aged) cohort, however, only the lowest dose reliably increased lifespan, while higher doses had mixed effects. And in the tenth (oldest) cohort, metformin proved toxic at all dosage levels, “with a large population of drug-exposed animals dying within first 24h of treatment.”

The researchers concluded that “Our tests thus revealed an age-dependent decrease in metformin tolerance, which culminated in late-life toxicity of all metformin doses tested, indicating possible safety risks of late-life metformin administration.”

The researchers used human skin-cell cultures to study at a molecular level how this works. Mitochondria use oxygen to produce ATP, the molecular “fuel” consumed in nearly all biological processes. When metformin restricts oxygen intake in younger human cells, the cellular metabolism adapts by kicking ATP production into a higher gear. As a result, ATP levels remain steady.

But as we age and our mitochondria deteriorate, our cells lose their adaptability. As a result, in late-life cells exposed to metformin, the German team observed a strong decline in levels of ATP. Deprived of ATP, the cells died.

Think of metformin like one of those altitude-training masks that runners wear. Just as the mask promotes the runner’s cardiovascular health by restricting intake of oxygen, so metformin seems to promote mitochondrial health by restricting the cell’s intake of oxygen. But what works for the young might be dangerous to the elderly, which is why you don’t often see eighty-year-olds running around in altitude-training masks. Their cardiovascular health is too fragile for such rigorous work.

The German team’s findings on metformin have implications for other anti-aging treatments that work by inducing stress. The researchers note that metformin works by the same mechanism as “dietary restriction” (DR), a lifestyle practice often touted for its anti-aging benefits. Recent research has suggested that DR, like metformin, may be less effective when adopted for the first time in old age. The German team therefore “questions whether longevity interventions, such as metformin and DR, which act via induction of metabolic stress, are suitable for old organisms, affected by mitochondrial frailty and impaired metabolic plasticity.”

It’s almost certainly a mistake to wait until old age to think about longevity. The time to start training the body for longevity is when it’s still young, healthy, and adaptable. An ounce of prevention is worth a pound of cure, as they say. And nowhere is this more true than in the inexorable, yet postponable decline of the body due to age.

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