Newsletter #290

Why do our bodies fall apart as we get older? In order to begin to answer this question, you need to zoom in, all the way down to the level of our tissues and cells.

One of the key mechanisms of aging is cellular senescence. In brief, normal cells enter this state in response to stress or damage. This is not necessarily a bad thing, in itself, as this program prevents cells from becoming cancerous. However, senescent cells are metabolically active, secreting inflammatory molecules around themselves, and they create all kinds of trouble. And they don’t go away, which means that as people get older, they accumulate more and more of them.

Quite a bit of research has been dedicated to investigating drugs (senolytics) that could safely remove senescent cells, as well as the inflammation and physiological dysfunction that accompanies them. Encouragingly, some recent studies suggest that physical activity could function as a senolytic, and this may be one of the many mechanisms through which exercise improves health and battles the aging process.

It has been proposed that exercise could lower the burden of senescent cells in two major ways:

First, exercise could prevent the accumulation of senescent cells by thwarting the molecular pathways that cause senescence. Cells convert to the senescent state in response to stress, including inflammation, DNA damage, oxidative stress, and mitochondrial dysfunction. Physical activity counters all of these forms of stress, which means in theory that cells should be healthier and fewer need to switch on senescent programming.

Secondly, exercise may promote clearance of senescent cells that have already accumulated, by stimulating the immune system to remove them. Bouts of physical activity have been shown previously to trigger transient increases in immune cells, as well as deploy these cells to tissues in the body where they are needed.

From 10.1249/JES.0000000000000302

The vascular endothelium is a membrane that lines the walls inside of your blood vessels. The cells that make up this membrane control the width of the arteries, and their function is critical for good cardiovascular health. When they are unable to widen, blood flow is affected, and the blood vessels can become damaged. For this reason, endothelial dysfunction is regarded as an independent risk factor for heart disease.

Endothelial function tends to decline as people get older, and senescence of endothelial cells has recently been implicated as a driver of age-related endothelial dysfunction.

To examine the role of lifestyle factors in endothelial cell senescence, a team of researchers examined data from participants who differed in age and exercise habits. These adults had their cardiorespiratory fitness (VO2max) as well as their vascular endothelial function (flow-mediated dilation or FMD) assessed. Additionally, samples of endothelial cells were extracted from either the antecubital veins or the brachial arteries of these subjects. These endothelial cells were analyzed for an array of markers related to cellular senescence, such as p16, a tumor suppressor protein that is expressed highly in senescent cells.

When they compared levels of all of these factors, they found substantially greater levels in 60-year-old sedentary subjects, compared to younger 22-year-old sedentary counterparts. For instance, levels of p16 were 128% greater in endothelial cells found in the antecubital veins of the older sedentary participants, compared to the younger sedentary subjects.

Next, they decided to look at samples of endothelial cells from older adults who were regular exercisers. Older exercising adults had markedly lower levels of senescence markers, compared to sedentary people of the same age. In fact, expression of markers of senescence in the older athletes was similar to that of the younger adults.

In other words, exercising appears to have prevented the age-related increase in senescent cells in the vascular endothelium.

A similar relationship emerged when the researchers compared measurements of endothelial function via flow-mediated dilation, which is basically a measurement of the capacity of an artery to widen in response to increased blood flow. Flow-mediated dilation was substantially reduced in sedentary older adults compared to the young adults ((4.1 ± 0.7% vs. 8.9 ± 0.9%), indicating endothelial dysfunction. No surprise there. But older exercise-trained adults had similar FMD to the younger participants.

Finally, lower levels of markers of senescence were all associated with greater flow-mediated dilation, suggesting a causal relationship between vascular endothelial senescence and endothelial dysfunction.

Prior research has established that aerobic exercise protects against age-related deterioration of endothelial function, and this study seems to indicate that reduction in senescent cells within blood vessel walls may be a key mechanism explaining this link.

Bouts of physical activity elicit a strong and multifaceted immune response. The innate immune system, in particular, is thought to play a role in recovery from strength training, as well as exercise adaptations. When you engage in resistance training, your muscle fibers sustain micro-tears, which is accompanied by a temporary inflammatory response. This process attracts macrophages, which infiltrate the damaged tissue and help promote muscle repair and growth. Macrophages are sort of like Pac-Man — they gobble up pathogens, cellular debris, and other stuff you don't want hanging around in the body. Importantly, studies using cell cultures suggest that macrophages are capable of attacking and clearing senescent cells.

To test this potential mechanism, researchers in Taiwan recruited 12 college students who had a background of sports participation. All subjects participated in two trials, which were devised to examine the impact of single exercise bouts on senescent cells, as well as the role of protein availability around exercise.

In one session, they ingested a low protein supplement before and after performing a resistance training workout. In the other session, the same protocol was done, except that they consumed a high protein supplement. Before and after both workouts, muscle biopsies were taken from the participants' legs, in order to assess macrophage infiltration in muscle tissue, as well as levels of senescent cells (measured via the marker p16).

Two days after exercise, the researchers found that immune cell infiltration in skeletal muscle had increased in both groups, and this resulted in depletion of senescent cells around the muscle tissue. Interestingly, the amount of protein being consumed around the training session affected the magnitude of this response. Specifically, levels of immune cells in the leg muscles increased by 82% in the high protein trial and by 230% in the low protein trial. And exercising while consuming the low protein diet led to greater clearance of senescent cells.

This appeared to be due to a stronger inflammatory signal when the men trained with low protein availability. Low protein delays the resolution of inflammation post-workout, which appears to amplify the immune response, and in turn could increase clearance of senescent cells.

Unfortunately, as you might expect, this comes with a pretty big tradeoff, with respect to gainz.

In a separate trial, the researchers found that 12 weeks of resistance training while on that low protein regimen led to zero increases in muscle mass, which they measured through DEXA. (So you should probably still consume protein around your workouts, even if it means less of a senolytic effect)

This is a powerful illustration of how exercise functions as a stressor, and the capacity of the body to adapt to that stress. As the researchers state, "Given the fact that resistance exercise increases muscle damage, the present results on senescent cell elimination provide an explanation on how a destructive challenge may bring benefit for human survival."

🍷 “Red wine headaches” may be due to high levels of a polyphenol in red grapes.

For a long time, some people have reported that red wine, but not other alcoholic beverages, causes headaches. I’ve always been skeptical of this purported phenomenon but it seems like maybe there’s something to it.

Red wine contains much higher levels of phenolic compounds than other alcoholic beverages — 10-fold greater than white wine. This is the main redeeming feature of red wine from a health standpoint, but it also might have some unpleasant side effects.

Researchers recently determined that quercetin, a phenolic compound found abundantly in red wine, inhibits one of the enzymes that helps metabolize alcohol. In susceptible individuals, this leads to higher levels of acetaldehyde, a metabolite of ethanol which is partially responsible for the headache that you get when you’re hungover.

Now that the days have gotten shorter in the Northern hemisphere and a lot of us are seeing less sunshine, making sure that you’re getting your vitamin D is paramount. Vitamin D appears to work synergistically with vitamin K2, so it makes a lot of sense to supplement them together. I’ve used this brand for a couple of years now, and their products are lab-tested to ensure that you’re actually getting what you paid for.

In this course, we:

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