Hallmark 8: Cellular Senescence
What is Cellular Senescence?
Our body’s cells must divide and replenish themselves to keep our tissues functioning. But, when a cell accumulates too much damage, allowing it to continue dividing could be dangerous. Normally, faulty or worn-out cells are removed through apoptosis - a kind of programmed cell death, like a tidy recycling system. Senescent cells, however, are different: instead of neatly bowing out, they slip into a strange half-life.
In this state, they remain alive and metabolically active but stop dividing. They resist the usual signals that would clear them away, making them stubborn “hang-arounds” in our tissues. Because of this uncanny persistence, they’re often nicknamed “zombie cells.” At first, senescence serves a protective role, preventing damaged cells from becoming cancerous. But when too many of these cellular “ghosts” accumulate, they start to haunt our tissues and disrupt healthy function.
Adding to the problem, senescent cells change the way they behave. They begin releasing a mix of signalling molecules known as the senescence-associated secretory phenotype (SASP). In small, short-lived bursts, SASP can be useful, calling in the immune system to help with tissue repair. But when senescent cells linger and SASP becomes chronic, it stirs up persistent inflammation, undermines nearby healthy cells, and contributes to tissue decline with age.
How Does it Happen and Why Does it Contribute to Ageing?
How Do Cells Become Zombies?
There isn’t just one road to senescence, cells can arrive at this half-life through several distinct pathways, each with its own trigger and consequence [1].
Replicative Senescence
What happens: As we spoke about in the telomere attrition hallmark, each cell division shaves down its telomeres, the protective caps of its DNA. Once they become too short, the cell hits a critical limit and freezes in place - like a clock running out of ticks.
Why it matters: It’s a safeguard against faulty copies, but the buildup of these frozen “zombies” gradually weakens tissue renewal [2}.
Stress-Induced Senescence
What happens: Stresses like UV light, toxins, oxidative damage, or relentless growth signals overwhelm a cell. When the stress alarms can’t be switched off, the cell shuts down division [3].
Why it matters: These conditions pile up with age (and lifestyle choices can add fuel), pushing more cells into this zombie state and leaving tissues vulnerable.
The SASP Effect
What happens: Senescent cells don’t rest quietly. They release a cocktail of inflammatory signals, the senescence-associated secretory phenotype (SASP), that summon the immune system for cleanup [4].
Why it matters: In youth, the immune system clears them out. But with age, more zombies linger, and their constant signalling drives chronic inflammation, damages neighbours, and even drags other cells into the same fate.
In essence: Senescence begins as a smart defence against danger, but when too many zombie-like cells stick around, their presence haunts tissues with chronic inflammation and declining repair capacity - key ingredients in the ageing process.
Accumulation and Organ‑Specific Effects
When we’re young, senescent cells don’t usually stick around for long. The immune system spots them, clears them out, and fresh cells take their place. With age, though, two things change: more cells are pushed into senescence as damage builds up, and the immune system becomes less efficient at removing them. The result is a steady buildup of these “zombie cells” across our tissues.
Interestingly, not all organs are equally vulnerable. In studies with mice, older livers, lungs, skin, and spleens were found to have nearly twice as many senescent cells as in youth, while tissues like the heart and skeletal muscle showed little accumulation [6]. This suggests some organs are more prone to senescent “haunting” than others. Even so, experiments have shown that introducing just a tiny number of senescent cells (around 1 in 10,000) can tip the balance toward frailty and shorten lifespan [7]. Clearing them, on the other hand, improves strength, resilience, and overall health.
This double-edged nature makes senescence what scientists call an “antagonistic hallmark.” Early in life it’s protective, preventing cancer and supporting repair. But later, its persistence fuels chronic inflammation, drains stem-cell reserves, and promotes tissue scarring. Senescent cells also aggravate other hallmarks of ageing such as mitochondrial decline, epigenetic drift, and loss of protein quality control. This is likely why reducing their burden in experimentation has had positive effects such as delayed cataracts, improved heart performance, reduced brain inflammation, and even extended lifespan.
Can We Slow Down Senescence to Slow Ageing?
Senolytics: Directly Targeting Senescent Cells
One strategy for tackling senescence is to wipe the zombies out altogether. Senolytic drugs are designed to do just that: they exploit the fact that senescent cells resist normal cell death by clinging to survival pathways. By blocking these lifelines, senolytics selectively push senescent cells over the edge [8].
The first widely studied pair, dasatinib and quercetin, was discovered by James Kirkland’s team and shown to clear senescent cells in mice, improving healthspan. Other drug classes target survival proteins (like the BCL-2 family) or growth pathways, while natural compounds such as fisetin (a flavonoid found in strawberries) also show senolytic effects [9].
With nearly 90 clinical trials underway worldwide, researchers are still uncovering where and how senolytics will deliver the most benefit. Excitingly, even existing drugs are being repurposed, like the diabetes drug canagliflozin, which in mice enhanced immune clearance of senescent cells, reduced inflammation, and extended lifespan [10].
Senomorphics Quieting the Noise
Senomorphics work by focusing on calming senescent cell’s disruptive signals, the SASP we spoke about above. These drugs turn down the volume of inflammation without eliminating the cells themselves.
Compounds like metformin, rapamycin, and ruxolitinib suppress key signalling pathways (mTOR and JAK) that drive SASP production. In animals, this dampening of inflammatory chatter improves metabolism and extends lifespan. Metformin, in particular, is being tested in older adults for its potential to reduce SASP, boost mitochondrial function, and improve resilience [11]. Some researchers even imagine “senescence vaccines” that could prime the immune system to better control these noisy cells.
Enhancing Clearance - Helping the Body Do Its Thing
Senescent cells pile up partly because the immune system struggles to recognise and remove them as we age. Strengthening immune surveillance may therefore be just as important as drugs. For instance, pre-clinical research shows that boosting the activity of immune sentinels like T-cells and natural killer cells helps the body clear senescent cells more effectively [12].
And while advanced therapies are in development, everyday choices still matter!
Lifestyle Approaches to Keep Senescent Cells in Check
While drugs and lab discoveries grab headlines, everyday choices remain some of the most powerful tools for influencing how senescent cells build up in the body. Diet, movement, rest, and toxin exposure all shape how quickly our cells edge toward that zombie-like state.
Move for Mitochondria and Immunity: Regular activity is a potent anti-senescence signal. Both aerobic and resistance exercise support mitochondrial turnover, enhance immune surveillance, and help maintain muscle mass. In mice, exercise has been shown to reduce senescent immune cells and improve glucose metabolism; human trials are now underway to see if these benefits translate directly to people. Aim for at least 150 minutes per week of moderate activity, ideally mixing cardio with strength training [13].
Nourish with Plants and Polyphenols: A diet rich in vegetables, fruits, legumes, whole grains, and healthy fats supplies antioxidants and polyphenols that blunt oxidative stress. Certain foods - like mushrooms, soy, and wheat germ - are naturally high in spermidine, a compound linked to autophagy and longevity. Beyond its role as a caloric-restriction mimetic, spermidine has also shown potential as a senomorphic, helping to tone down the harmful signals (SASP) released by senescent cells.
Caloric restriction/Intermittent Fasting: Trials of modest caloric restriction (about 12% fewer calories over two years) in healthy adults showed reductions in senescence markers, alongside better insulin sensitivity and metabolic health. Intermittent fasting offers another route [15].
Prioritise Sleep and Stress Relief: Sleep and stress hormones are deeply tied to cellular health. Chronic stress and disrupted sleep elevate cortisol and inflammation, which drive senescence. Mindfulness, relaxation practices, and maintaining a consistent sleep rhythm support immune balance and reduce the metabolic strain that accelerates cell ageing [16].
Avoid Accelerators: Smoking, excessive alcohol, and environmental toxins are direct accelerants of senescence, inflicting DNA damage and oxidative stress. Avoiding these exposures is one of the simplest ways to protect cellular integrity. Maintaining a healthy weight is equally important, as obesity and metabolic syndrome are strongly linked to higher senescence burden [15].
Conclusion
Cellular senescence captures the paradox of ageing: a mechanism that shields us in youth can slowly undermine us as it lingers. Scientists are working on ways to silence or clear these “zombie cells,” but while those therapies remain experimental, we’re not powerless. How we eat, move, rest, and manage stress shapes the pace at which senescent cells accumulate. By tending to these everyday levers, we can help our tissues stay resilient for longer.
References:
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Author: Georgia Pilling
