The Four Horsemen: heart disease, cancer, neurodegenerative disease, or type 2 diabetes and related metabolic dysfunction. To achieve longevity–to live longer and live better for longer– we must understand and confront these causes of slow death.
Longevity has two components. The first is how long you live, your chronological lifespan, but the second and equally important part is how well you live-the quality of your years. This is called healthspan, and it is what Tithonus forgot to ask for.
The first era, exemplified by Hippocrates but lasting almost two thousand years after his death, is what can be called Medicine 1.0. Its conclusions were based on direct observation and abetted more or less by pure guesswork, some of which was on target and some not so much. Hippocrates’s major contribution was the insight that diseases are caused by nature and not by actions of the gods, as had previously been believed. That alone represented a huge step in the right direction. So it’s hard to be too critical of him and his contemporaries. They did the best they could without an understanding of science or the scientific method. You can’t use a tool that has not yet been invented.
Medicine 2.0 arrived in the mid-nineteenth century with the advent of the germ theory of disease, which supplanted the idea that most illness was spread by “miasmas,” or bad air. This led to improved sanitary practices by physicians and ultimately the development of antibiotics. But it was far from a clean transition; it’s not as though one day Louis Pasteur, Joseph Lister, and Robert Koch simply published their groundbreaking studies, and the rest of the medical profession fell into line and changed the way they did everything overnight. In fact, the shift from Medicine 1.0 to Medicine 2.0 was a long. bloody slog that took centuries, meeting trench-warfare resistance from the establishment at many points along the way.
Could the centenarians merely be lucky? Certainly, their age alone makes them extreme statistical outliers. As of 2021, there were just under 100,000 centenarians in the United States, according to the Census Bureau. And although their number has increased by nearly 50 percent in just two decades, the over-one-hundred age group still represents only about 0.03 percent of the population, or about 1 out of every 3,333 of us.
After ten decades of age, the air gets pretty thin, pretty quickly. Those who live to their 110th birthday qualify for the ultra-elite cadre of “supercentenarians,” the world’s smallest age group, with only about three hundred members worldwide at any given time (although the number fluctuates). Just to give you a sense of how exclusive this club is, for every supercentenarian in the world at this writing, there are about nine billionaires.
You may have heard of this gene, which is called APOE, because of its known effect on Alzheimer’s disease risk. It codes for a protein called APOE (apolipoprotein E) that is involved in cholesterol transport and processing, and it has three variants: e2, e3, and e4. Of these, e3 is the most common by far, but having one or two copies of the e4 variant seems to multiply ones risk of developing Alzheimer’s disease by a factor of between two and twelve.
The e2 variant of APOE, on the other hand, seems to protect its carriers against dementia-and it also turns out to be very highly associated with lon-gevity. According to a large 2019 meta-analysis of seven separate longevity studies, with a total of nearly thirty thousand participants, people who carried at least one copy of APOE e2 (and no e4) were about 30 percent more likely to reach extreme old age (defined as ninety-seven for men, one hundred for women) than people with the standard e3/3 combination. Mean-while, those with two copies of e4, one from each parent, were 81 percent less likely to live that long, according to the analysis.
FOXO3 belongs to a family of “transcription factors” which regulate how other genes are expressed – meaning whether they are activated or “silenced?” Its responsibilities are vast, encompassing a variety of cellular repair tasks, regulating metabolism, caring for stem cells, and various other kinds of housekeeping, including helping with disposal of cellular waste or junk. But it doesn’t do the heavy lifting itself, like the mopping, the scrubbing, the minor drywall re. pairs, and so on. Rather, it delegates the work to other, more specialized genes–its subcontractors, if you will. When FOXO3 is activated, it in tur activates genes that generally keep our cells healthier. It seems to play an important role in preventing cells from becoming cancerous as well.
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 Grandmas 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 nest chapter) and releasing energy stored in fat cells.
More importantly, AMPK works to inhibit the activity of mTOR, the cel. lular 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 TOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating an important cellular recycling process called autophagy, which means “self-eating” (or better yet, “self-devouring”).
Source : Outlive: The Science & Art of Longevity by Peter Attia, Bill Gifford
Goodreads : https://www.goodreads.com/book/show/61153739-outlive
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Thinking Beyond Science 
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