Lifespan: Why We Age—and Why We Don't Have To

by David A. Sinclair

They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. As we will see later, the loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.

Here’s the important point: there are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets, and exposure to hot and cold temperatures (I discuss this in chapter 4). That’s called hormesis.28 Hormesis is generally good for organisms,

What place does a diabetes medication have in a conversation about prolonging vitality? Perhaps it would have no place at all if not for the fact that, a few years ago, researchers noticed a curious phenomenon: people taking metformin were living notably healthier lives—independent, it seemed, of its effect on diabetes.16 In mice, even a very low dose of metformin has been shown by Rafael de Cabo’s lab at the National Institutes of Health to increase lifespan by nearly 6 percent, though some have argued that the effect is due mostly to weight loss.17 Either way, that amounts to the equivalent of five extra healthy years for humans, with an emphasis on healthy—the mice showed reduced LDL cholesterol levels and improved physical performance.18 As the years have gone by, the evidence has mounted. In twenty-six studies of rodents treated with metformin, twenty-five showed protection from cancer.19 Like rapamycin, metformin mimics aspects of calorie restriction. But instead of inhibiting TOR, it limits the metabolic reactions in mitochondria, slowing down the process by which our cellular powerhouses convert macronutrients into energy.20 The result is the activation of AMPK, an enzyme known for its ability to respond to low energy levels and restore the function of mitochondria. It also activates SIRT1, one of my lab’s favorite proteins. Among other beneficial effects, metformin inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.21...

Most of us assume that the effects of a pill like metformin would take years to produce any appreciable effect on aging, but maybe not. An admittedly small study of healthy volunteers claimed that the DNA methylation age of blood cells is reversed within a week and, astoundingly, only ten hours after taking a single 850 mg pill of metformin.26 But clearly more work is needed with greater numbers of subjects to know for sure if metformin can delay the aging clock over the long run.

Meanwhile, on a parallel path, researchers, including us, were homing in on a chemical called nicotinamide mononucleotide, or NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it,40 and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.

That’s what the Mayo Clinic’s James Kirkland has done. He needed only a quick course of two senolytic molecules—quercetin, which is found in capers, kale, and red onions, and a drug called dasatinib, which is a standard chemotherapy treatment for leukemia—to eliminate the senescent cells in lab mice and extend their lifespan by 36 percent.4 The implications of this work cannot be overstated. If senolytics work, you could take a course of a medicine for a week, be rejuvenated, and come back ten years later for another course. Meanwhile, the same medicines could be injected into an osteoarthritic joint or an eye going blind, or inhaled into lungs made fibrotic and inflexible by chemotherapy, to give them an age-reversal boost, too. (Rapamycin, the Easter Island longevity molecule, is what’s known as a “senomorphic” molecule, in that it doesn’t kill senescent cells but does prevent them from releasing inflammatory molecules, which may be almost as good.5)

larger vision that might give all of life coherence

take 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into my homemade yogurt) and 1 gram of metformin.7 • I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin. • I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes. • I try to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week.