How HIIT Fights “Zombie Cells”
This Week’s Research Highlight
When Cells Stop Working
What causes our bodies to break down as we age?
Well, at the level of our cells and tissues, countless molecular changes occur, and one key culprit driving these changes is cellular senescence.
When normal cells experience stress or damage, they can enter a “senescent” state. In this state, they stop dividing but don’t die—earning the nickname “zombie cells.” This process helps protect us by preventing damaged cells from turning cancerous.
But there’s a catch. These senescent cells release inflammatory signals that disrupt the environment around them. Worse, they stick around and build up as we age, fueling inflammation and contributing to age-related decline.
Just as one example, we now know that senescent cells accumulate in cartilage other joint tissues as we get older, and in response to injury. Inflammatory mediators released by senescent cells hinder the ability of chondrocytes (the cells that maintain cartilage) to repair and regenerate tissue, causing age-related joint issues.
Remarkably, studies in rodent and human tissues have revealed that targeting senescent cells with senolytic drugs (which eliminate senescent cells) can reduce inflammation, improve joint function, and even slow the progression of osteoarthritis.
As a result, a ton of research has been dedicated to investigating compounds that could safely remove senescent cells. While such approaches are under development, scientists have been examining whether lifestyle factors could help manage the burden of senescent cells.
Exercise has emerged as one such candidate. Animal models demonstrate that physical activity leads to reductions in biomarkers of senescence. This makes intuitive sense, as we know that exercise positively affects virtually every system in the body, from metabolism to immunity. However, it remains unclear what type of exercise regimen is most effective.
Here’s why this matters: different intensities of physical activity engage different energy systems in the body. For instance, walking primarily depends on aerobic metabolism, while hard interval training pushes us into anaerobic energy production. This creates distinct metabolic signals in our tissues, which in turn could influence how the body handles senescent cells.
A new study has tackled this conundrum head-on, by directly comparing how different exercise intensities affect markers of cellular senescence in muscle tissue in human participants.
Let’s take a look at what they found.
Inside the Study
To understand how exercise affects aging at the cellular level, Taiwanese researchers recruited nine young men who didn't regularly exercise. The team started by measuring each participant's maximal aerobic power — the highest power output they could sustain on a stationary bicycle while still relying on oxygen for energy. Think of this as the ceiling of the aerobic energy system, the point where your body is working at 100% of its oxygen-processing capacity.
Then, all participants completed two different cycling protocols, carefully measuring how their muscle tissue responded to each one.
The first was steady-state exercise (SSE) at 60% of maximal aerobic power. This is like a moderate-paced bike ride where you're a little out of breath, but can still maintain a conversation. At this intensity, your body can keep up with its oxygen needs, allowing you to exercise for longer periods.
The second was high-intensity interval exercise (HIIE) at 120% of maximal aerobic power. At this intensity, participants were pushing beyond their aerobic capacity — producing more power than their body could support through oxygen alone. Since this isn't sustainable for very long, participants alternated between 20-second bursts of intense cycling and 20 seconds of rest.
To ensure a fair comparison, researchers calculated the total amount of work performed during each session and made sure they were the same. This way, any differences in cellular responses would truly be due to intensity, rather than the total amount of activity.
What They Found
To examine how the muscle tissue responded, researchers collected small muscle samples from participants' thigh muscles (specifically, the vastus lateralis) at three time points: before exercise, immediately after, and 24 hours later. These samples were analyzed for various markers of cellular aging, inflammation, and DNA damage.
The most compelling finding came from measuring p16INK4a, a key marker of cellular aging.
p16INK4a is sort of like a cellular stop sign. Its main job is to prevent cells from dividing and reproducing, which is why scientists call it a "cyclin-dependent kinase inhibitor" — it blocks the cellular machinery responsible for cell division. As cells approach senescence, they produce more and more p16INK4a, so measuring the amount of p16INK4a gives us a good idea of how many senescent cells are present in a given tissue.
Twenty-four hours after the high-intensity exercise, levels of p16INK4a had dropped by 57%. This suggests that the exercise session had effectively cleared away many of these senescent cells, essentially nudging the muscle tissue into a state that appears to have a younger biological age.
Cellular senescence marker p16INK4a significantly decreased 24 hours after high-intensity interval training. Meanwhile, at a similar amount of cycling work, steady state exercise failed to elicit changes in p16INK4a.
In contrast, moderate-intensity steady-state exercise (SSE) produced minimal changes in these cellular markers — despite participants performing the same amount of total work.
The Stress-Adapt Cascade
High intensity exercise triggers specific stress responses in muscle tissue, which lead to an array of beneficial adaptations.
First of all, HIIT causes rapid lactate production and decreased pH (acidosis). This, by the way, is responsible for the infamous “burn” that you experience when lifting weights or sprinting.
Acidosis acts as a danger signal to the immune system, attracting macrophages, which infiltrate the muscle tissue. During this time, they help promote muscle repair and growth, and they also gobble up cellular debris and other stuff that you don’t want hanging around in the body, including senescent cells.
Sure enough, when the researchers compared the thigh muscle biopsies of these men, they found that immune cell infiltration into muscle ramped up 1.2-fold immediately after the high-intensity interval workout.
Cell infiltration in thigh muscle after steady state exercise versus high intensity interval exercise
But that’s not all. The metabolic perturbations of high-intensity exercise also create oxidative stress, which can lead to DNA damage in local cells.
When the researchers compared DNA strand breaks in the muscle biopsies, they observed a 1.3-fold increase in fragmented DNA immediately after the high intensity interval workout.
Now, so far this actually sounds kind of bad — after all, DNA damage is itself a driver of cellular senescence!
DNA strand breaks after both exercise regimens
But if you look at the graph, you’ll notice that the number of DNA strand breaks after HIIE returns to baseline at the 24 hour mark.
Here’s why: DNA damage, and the associated inflammation, also acts as a danger signal to the immune system, drawing the attention of white blood cells. Following high-intensity exercise, levels of γ-H2AX rose in parallel to DNA damage. γ-H2AX acts like an emergency flare, which marks the damage site and helps coordinate the repair crew. 👷🏼 🚜
γ-H2AX levels after SSE and HIIE
Taken together, this coordinated stress response — combining metabolic stress (acidosis) and DNA damage/repair processes — appears to trigger a kind of cellular spring cleaning in our muscles.
Like many beneficial adaptations in biology, it follows a pattern known as hormesis, wherein temporary stress ultimately makes a system stronger.
No Pain, No Gain
To confirm that the stress response from high-intensity exercise is necessary for cellular cleanup, the researchers conducted a clever follow-up study.
They had participants complete the same high-intensity interval workout under two conditions: once while taking ibuprofen, and once with a placebo.
The results were striking. When the inflammatory cascade associated with HIIT was suppressed by ibuprofen, the exercise's senolytic effects were dramatically blunted.
This proves that the stress and discomfort of HIIT is actually a necessary trigger for beneficial regeneration.
So next time you’re pushing yourself through a tough workout, bear in mind that the temporary suffering is just the kick-start of a well-orchestrated renewal process for your body. ✨
To investigate how exercise intensity affects cellular aging markers in muscle tissue, researchers had healthy young men complete two different cycling protocols: steady-state exercise at 60% of maximal aerobic power, and high-intensity intervals at 120% of maximal aerobic power. Both protocols were matched for total work output. Muscle biopsies were taken before exercise, immediately after, and 24 hours later. The high-intensity workout triggered significant cellular changes: immune cell infiltration increased 1.2-fold, DNA damage markers rose 1.3-fold, and DNA repair signals increased 1.1-fold immediately after exercise. Most importantly, markers of cellular senescence (p16INK4a) decreased by 57% after 24 hours. The steady-state exercise produced no significant changes in these markers. A follow-up study using ibuprofen confirmed that the inflammatory response was necessary for these benefits — when inflammation was blocked, the senescent cell-clearing effects were significantly reduced.
Random Trivia & Weird News
💌 To combat falling birth rates, the South Korean government has been actively playing matchmaker.
Last year, the country hit a record-low fertility rate of 0.72 children per woman. Their solution? Turn the entire country into a government-sponsored dating service.
Among the initiatives:
- A Buddhist temple runs a dating program called "I am Jeolo" (a play on the dating show "I am Solo"), where singles stay overnight at temples to find love.
- Couples who meet through government programs can receive escalating financial rewards: $500 for becoming a couple, $1,000 for having family meetings to discuss marriage, and $20,000 when they actually tie the knot.
- The government has opened up 28 public facilities as free wedding venues, including museums, art centers, and parks.
Perhaps most remarkably, newlywed couples can rent government-subsidized apartments for as little as 10,000 won (about $7.50) per month in some regions.
Will these interventions move the needle? Only time will tell.
Photo credit: Korean Buddhist Foundation for Social Welfare
Podcasts We Loved This Week
- Charles Fain Lehman: A mysterious health wave is breaking out across the U.S. Via Plain English with Derek Thompson.
- Simon Hill: Five reasons to supplement with creatine. Via The Proof.
Products We Like
Qualia Senolytic
Flavonoids are a diverse family of compounds found in fruits, vegetables, and other plant foods. These molecules give many fruits and vegetables their vibrant colors and play crucial roles in plant defense against environmental stresses. When we consume these compounds, they can trigger beneficial adaptations in our own cells — including the clearance of senescent cells.
Qualia Senolytic combines two flavonoids that have been shown to have this effect. The formulation centers around fisetin, a flavonoid found naturally in strawberries and other fruits. If you’d like to know more about fisetin, we interviewed a researcher (Pam Maher) who has been investigating the compound for years. It also features quercetin, found in apples and onions, another plant compound that has been extensively studied in cellular aging research.
Unlike most supplements, this is something you use cyclically, rather than daily – the standard dosage is six pills per day for two days, to be completed once per month.
humanOS Catalog Feature of the Week
Optimizing Nutrition with Smoothies
To access this course…
- Login here
- Click mini-courses (side nav on desktop, top right nav on mobile)
- Scroll down to find Smoothies
This week, we’d like to highlight our course on Optimizing Nutrition with Smoothies.
Despite the name, this course is more of a deep dive into the health-promoting properties of phytochemicals. Importantly, this course reveals how some of these powerful plant compounds can help clear away aging cells and promote tissue rejuvenation.
In the course, you’ll learn about natural senolytic fisetin, but that's just the beginning. From brain-boosting anthocyanins in blueberries to metabolism-enhancing catechins in green tea, you'll find out how strategic smoothie combinations can deliver therapeutic doses of health-promoting compounds that are tricky to acquire through regular eating.
Wishing you the best,
