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 Dr. Frank Lipman sits on a chair, cross-legged, arm resting on the back of the chair, lightly touching his other hand that is resting on his thigh. He is wearing blue denim, a blue dress shirt and a navy textured blazer and black glasses. He is smiling, showing his front teeth looking off to the side.

Dr. Frank Lipman

Chief Medical Officer at THE WELL

Updated: 04/04/2024

In last week’s post, I introduced readers to what scientists call “the hallmarks of aging,” the specific biochemical processes that are happening in your body every day, every second, which, taken together, take us from our physical peak in our twenties right on through to the end of our lives.

The idea, as I explained, is “know your enemy,” as in, if we can identify what’s going on in the body, we can take steps to fight back against it, whether that’s healthy lifestyle choices now or, down the line, with the help of new treatments being studied in the lab today. I’ve already covered the first three hallmarks — genomic instability, telomere attrition and epigenetic alterations. In this post, we’ll take a look at the next three hallmarks — namely, proteostasis, deregulated nutrient sensing, mitochondrial dysfunction — and what you need to know them:

4. Loss of proteostasis — the protein balancing act

If, by now, you’re asking yourself, what is it that the DNA in our genes actually does, here’s the short answer — it orchestrates the production of proteins. Proteins are the workhorses of the body. They form the body’s structure – bones, muscle, connective tissue – and they make up the enzymes and hormones that keeps our biochemistry humming inside that structure. And, in part, our health depends on maintaining the proper balance between making new proteins and getting rid of old ones, or, to use the scientists’ term, proteostasis. As with all the other hallmarks, with age the body grows less adept at this balancing act. Proteins have to assume a specific shape to do their specific job. But over time, more misshapen proteins are produced, as well as more proteins that fail to come apart at the end of their shelf life and just stick around, gumming up the works. These misfires contribute to the burden of diseases of aging, especially neurodegenerative diseases like Alzheimer’s. The healthy lifestyle choices we know are good for us are likely working to make our protein machinery more efficient and more resistant to age-related break-down. Some researchers believe that drugs may be developed that will directly repair that machinery. Until then, it’s all about lifestyle with the possibility of a supplemental assist. Ideally working with an integrative practitioner, you may want to explore supplements like spermidine, berberine, curcumin and quercetin.

5. Deregulated nutrient sensing or fine-tuning your metabolism

Yes, I know, this term, like some of the other hallmarks, sounds like a mouthful. But that’s only fitting – it describes the crucial relationship between how much and how well we eat, and how we age. The basic idea here is that our nutritional needs change as we age. When we’re young our metabolic (or “nutrient sensing”) dials are turned way up, so the calories we take in, especially the proteins, are, as much as possible, devoted to growth, so we can reach our full adult size and strength. But once we reach maturity, our priorities shift, and more energy needs to be devoted to cell maintenance and repair. If our nutrient sensing systems don’t get this new balance right, we’ll take in too many calories and invest them in the wrong places. The result is too much oxidative stress at the molecular level (those “free radicals”) and likely too much pro-inflammatory fat accumulating on the body. That’s a prescription for aging poorly and becoming more and more vulnerable to the diseases of aging like heart disease, neurodegenerative disease and cancer.

So, what are these nutrient-sensing systems? Most of us are probably familiar with our insulin system which helps determine how much of the carbs we eat are burned for energy and how much stored as fat. The mTOR system helps determine how much of the protein we consume goes to building new tissues and how much to maintaining what we’ve already got. The sirtuin system promotes a leaner, cleaner metabolism – it’s what the anti-aging compound resveratrol works through. There’s more but you get the idea.

For our part, we can help keep these systems on track with a low-carb/high veggie diet; intermittent fasting should provide an extra boost. Working with an integrative practitioner, you may want to explore supplements like NAD+ and possibly a pharmaceutical like metformin and conceivably rapamycin, a potent immune-system suppressor to be taken only under the strict supervision of a physician.

6. Mitochondrial dysfunction or when good energy goes bad

The mitochondria, as you’ve probably heard by now, are the powerhouses inside the cell that generate most of the juice that runs the body. But, like just about everything else the hallmarks describe, the power supply goes downhill over time. The mitochondria decline in number and they become increasingly susceptible to internal damage inflicted by the free radicals that are the toxic byproduct of all that energy production. Damaged mitochondria spew out yet more free radicals, a classic vicious circle. That can help set in motion any number of serious degenerative diseases as well as show up as the common symptom of fatigue, maybe the most common complaint I hear as my patients get older.

Fortunately, we can do something about it. Just as the mitochondria shrink with years of physical inactivity, they respond by becoming larger and more numerous when there’s increased demand. Physical activity is nature’s mitochondrial helper. Any kind of movement is a plus but more sustained cardio and strength work will pay extra dividends. Ditto subjecting yourself, and your cells, to mild stressors – for instance, intermittent fasting or taking cold showers. We call this kind of healthy stress “hormesis.” And of course, diet plays a role as well, especially polyphenol-rich whole foods. And don’t forget to take a vitamin D supplement.

So where do we go from here? What comes after proteostasis, deregulated nutrient sensing and mitochondrial dysfunction? See my post next week when I cover the next three hallmarks of aging, including: cellular senesence, stem cell exhaustion and altered intercellular communication.

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