summarize this "To scientists who study aging, the life-extending effect of rapamycin was
hugely exciting, but it also wasn’t exactly a surprise. It appeared to represent
the culmination of decades, if not centuries, of observations that how much
food we eat correlates somehow with how long we live. This idea goes all the
way back to Hippocrates, but more modern experiments have demonstrated,
over and over, that reducing the food intake of lab animals could lengthen
their lives.
The first person to really put the idea of eating less into practice, in a
rigorous, documented way, was not an ancient Greek or a modern scientist
but a sixteenth-century Italian businessman named Alvise Cornaro. A selfmade real estate developer who had become tremendously wealthy by
draining swamps and turning them into productive farmland, Cornaro (whose
friends called him “Luigi”) had a beautiful young wife and a villa outside
Venice with its own theater. He loved to throw parties. But as he neared forty,
he found himself suffering from “a train of infirmities,” as he put it—stomach
pains, weight gain, and continual thirst, a classic symptom of incipient
diabetes.
The cause was obvious: too much feasting. The cure was also obvious:
knock off the huge meals and parties, his doctors advised him. Not-Thin
Luigi balked. He didn’t want to give up his lavish lifestyle. But as his
symptoms became more and more unbearable, he realized that he had to
make a hard course correction or he would never get to see his young
daughter grow up. Summoning all his willpower, he cut himself back to a
Spartan diet that consisted of about twelve ounces of food per day, typically
in the form of some sort of chicken-based stew. It was nourishing, but not
overly filling. “[I] constantly rise from the table with a disposition to eat and
drink still more,” he wrote later.
After a year on this regimen, Cornaro’s health had improved dramatically.
As he put it, “I found myself…entirely freed from all my complaints.” He
stuck to the diet, and by the time he reached his eighties he was so thrilled to
have lived so long in such good health that he felt compelled to share his
secret with the world. He penned an autobiographical tract that he called
“Discourses on the Sober Life,” although it was emphatically not a teetotaler’s
screed, for he washed down his longevity stew with two generous glasses of
wine each day.
Cornaro’s prescriptions lived on long after he died in 1565. His book was
reprinted in several languages over the next few centuries, lauded by
Benjamin Franklin, Thomas Edison, and other luminaries, making it perhaps
the first bestselling diet book in history. But it was not until the mid-twentieth
century that scientists would begin rigorously testing Cornaro’s notion that
eating less can lengthen one’s life (or at least, the lives of laboratory animals).
We’re not talking about simply putting animals on Weight Watchers.
Caloric restriction without malnutrition, commonly abbreviated as CR, is a
precise experimental method where one group of animals (the controls) are
fed ad libitum, meaning they eat as much as they want, while the
experimental group or groups are given a similar diet containing all the
necessary nutrients but 25 or 30 percent fewer total calories (more or less).
The restricted animals are then compared against the controls.
The results have been remarkably consistent. Studies dating back to the
1930s have found that limiting caloric intake can lengthen the lifespan of a
mouse or a rat by anywhere from 15 to 45 percent, depending on the age of
onset and degree of restriction. Not only that, but the underfed animals also
seem to be markedly healthier for their age, developing fewer spontaneous
tumors than normally fed mice. CR seems to improve their healthspan in
addition to their lifespan. You’d think that hunger might be unhealthy, but the
scientists have actually found that the less they feed the animals, the longer
they live. Its effects seem to be dose dependent, up to a point, almost like a
drug.
The life-extending effect of CR seems to be almost universal. Numerous
labs have found that restricting caloric intake lengthens lifespan not only in
rats and mice (usually) but also in yeast, worms, flies, fish, hamsters, dogs,
and even, weirdly, spiders. It has been found to extend lifespan in just about
every model organism on which it has been tried, with the odd exception of
houseflies. It seems that, across the board, hungry animals become more
resilient and better able to survive, at least inside a well-controlled, germ-free
laboratory.
That doesn’t mean that I will be recommending this kind of radical caloric
restriction as a tactic for my patients, however. For one, CR’s usefulness
remains doubtful outside of the lab; very lean animals may be more
susceptible to death from infection or cold temperatures. And while eating a
bit less worked for Luigi Cornaro, as well as for some of my own patients,
long-term severe caloric restriction is difficult if not impossible for most
humans to sustain. Furthermore, there is no evidence that extreme CR would
truly maximize the longevity function in an organism as complex as we
humans, who live in a more variable environment than the animals described
above. While it seems likely that it would reduce the risk of succumbing to at
least some of the Horsemen, it seems equally likely that the uptick in
mortality due to infections, trauma, and frailty might offset those gains.
The real value of caloric restriction research lies in the insights it has
contributed to our understanding of the aging process itself. CR studies have
helped to uncover critical cellular mechanisms related to nutrients and
longevity. Reducing the amount of nutrients available to a cell seems to
trigger a group of innate pathways that enhance the cell’s stress resistance and
metabolic efficiency—all of them related, in some way, to mTOR.
The first of these is an enzyme called AMP-activated protein kinase, or
AMPK for short. AMPK is like the low-fuel light on the dashboard of your
car: when it senses low levels of nutrients (fuel), it activates, triggering a
cascade of actions. While this typically happens as a response to lack of
nutrients, AMPK is also activated when we exercise, responding to the
transient drop in nutrient levels. Just as you would change your itinerary if
your fuel light came on, heading for the nearest gas station rather than
Grandma’s house, AMPK prompts the cell to conserve and seek alternative
sources of energy.
It does this first by stimulating the production of new mitochondria, the
tiny organelles that produce energy in the cell, via a process called
mitochondrial biogenesis. Over time—or with disuse—our mitochondria
become vulnerable to oxidative stress and genomic damage, leading to
dysfunction and failure. Restricting the amount of nutrients that are available,
via dietary restriction or exercise, triggers the production of newer, more
efficient mitochondria to replace old and damaged ones. These fresh
mitochondria help the cell produce more ATP, the cellular energy currency,
with the fuel it does have. AMPK also prompts the body to provide more fuel
for these new mitochondria, by producing glucose in the liver (which we’ll
talk about in the next chapter) and releasing energy stored in fat cells.
More importantly, AMPK works to inhibit the activity of mTOR, the
cellular growth regulator. Specifically, it seems to be a drop in amino acids
that induces mTOR to shut down, and with it all the anabolic (growth)
processes that mTOR controls. Instead of making new proteins and
undergoing cell division, the cell goes into a more fuel-efficient and stressresistant mode, activating an important cellular recycling process called
autophagy, which means “self-eating” (or better yet, “self-devouring”).
Autophagy represents the catabolic side of metabolism, when the cell
stops producing new proteins and instead begins to break down old proteins
and other cellular structures into their amino acid components, using the
scavenged materials to build new ones. It’s a form of cellular recycling,
cleaning out the accumulated junk in the cell and repurposing it or disposing
of it. Instead of going to Home Depot to buy more lumber and drywall and
screws, the cellular “contractor” scavenges through the debris from the house
he just tore down for spare materials that he can reuse, either to build and
repair the cell or to burn to produce energy.
Autophagy is essential to life. If it shuts down completely, the organism
dies. Imagine if you stopped taking out the garbage (or the recycling); your
house would soon become uninhabitable. Except instead of trash bags, this
cellular cleanup is carried out by specialized organelles called lysosomes,
which package up the old proteins and other detritus, including pathogens,
and grind them down (via enzymes) for reuse. In addition, the lysosomes also
break up and destroy things called aggregates, which are clumps of damaged
proteins that accumulate over time. Protein aggregates have been implicated
in diseases such as Parkinson’s and Alzheimer’s disease, so getting rid of
them is good; impaired autophagy has been linked to Alzheimer’s disease–
related pathology and also to amyotrophic lateral sclerosis (ALS), Parkinson’s
disease, and other neurodegenerative disorders. Mice who lack one specific
autophagy gene succumb to neurodegeneration within two to three months.
By cleansing our cells of damaged proteins and other cellular junk,
autophagy allows cells to run more cleanly and efficiently and helps make
them more resistant to stress. But as we get older, autophagy declines.
Impaired autophagy is thought to be an important driver of numerous agingrelated phenotypes and ailments, such as neurodegeneration and
osteoarthritis. Thus, I find it fascinating that this very important cellular
mechanism can be triggered by certain kinds of interventions, such as a
temporary reduction in nutrients (as when we are exercising or fasting)—and
the drug rapamycin. (The Nobel Committee shares this fascination, having
awarded the 2016 Nobel Prize in Physiology or Medicine to Japanese
scientist Yoshinori Ohsumi for his work in elucidating the genetic regulation
of autophagy.)
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