Hallmark 10: Stem Cell Exhaustion
The Integrative Hallmarks of Ageing
There are four integrative hallmarks of ageing, the stage when earlier forms of cellular damage can no longer be balanced or repaired. From the original Hallmarks of Ageing framework, the integrative hallmarks include stem cell exhaustion, altered intercellular communication, chronic inflammation and gut dysbiosis. Together, these processes further disturb the body’s internal stability and directly drive the visible and functional changes we associate with ageing [1]. Among them, stem cell exhaustion plays a central role.
What Is Stem Cell Exhaustion?
You’ve probably seen adverts promising to repair, renew, and rejuvenate your skin. What they rarely promise is to regrow and that’s the crucial part, only your stem cells can do that!
Stem cells are the body’s original “master builders,” often described as shapeshifter cells due to their extraordinary ability to become almost any type of cell the body needs. This versatility, known as cellular plasticity, allows them to transform into specialised cells such as muscle, nerve, or blood cells, depending on the body’s demands. They usually lie dormant within tissues, springing into action only when repair or renewal is required, such as after injury or to replace lost cells [2].
Importantly, not all stem cells have the same shapeshifting capacity, there are a number of different types [3]:
Embryonic stem cells are the most flexible. They can become any cell in the body and are often used in research to understand how tissues form.
Adult stem cells live in different organs like the skin, gut, muscles, and bone marrow acting as localised repair cells. They can only become the types of cells needed in their own tissue.
Mesenchymal stem cells are a type of adult stem cell found in places like bone marrow and fat. They help form bone, cartilage, and fat as well as helping calm inflammation during healing.
Induced pluripotent stem cells are regular adult cells that scientists have “reset” back to a youthful, flexible state using the ‘Yamanaka factors’ (read below). They behave a lot like embryonic stem cells and are a powerful research tool.
They are essentially the body’s long-term repair reserves, able to renew themselves and replace many different types of cells. Stem cells are further supported by progenitor cells, which are their “next in line” descendants. Progenitor cells are more limited, they can only produce a narrow range of related cells, but they respond quickly when tissues need fast, focused repair [4].
Each organ has its own way of keeping itself in good repair using these stem and progenitor cell systems [5], for example:
Skin: Skin maintains itself through skin stem cells located in the base layer and around hair follicles working to continually replace lost skin cells and help close wounds.
Muscle: Muscle repair depends on satellite cells, a specialised group of muscle stem cells that activate when muscle fibres are stressed or injured.
Liver: The liver draws on ordinary hepatocytes (liver cells), which can act like stem cells by dividing rapidly when repair is needed. Liver progenitor cells provide extra support after more serious damage.
Lungs: The lungs rely on several types of airway and alveolar stem cells that renew the lining of the airways and the delicate air sacs.
Brain: The brain contains small groups of neural stem cells, mainly in areas linked to memory and learning, such as the hippocampus. These stem cells help form new neurons and support brain plasticity.
Pancreas: The pancreas uses progenitor cells within its ducts and other regions to replace cells and support recovery after inflammation or strain.
How Does It Happen and Why Does It Contribute to Ageing?
When we are young this process is effortless but, over time, stem cells grow fewer and less effective. They accumulate DNA damage, lose energy, and stop responding properly to repair signals. This gradual decline is called stem cell exhaustion and it’s one of the main reasons our bodies tend to heal more slowly with age [1,6]. As more stem and progenitor cells become damaged or inactive, organs struggle to keep up with routine repair.
Skin: Slower renewal leads to thinner, drier skin and delayed healing.
Muscle: Satellite cells lose strength, so damaged fibres repair poorly, contributing to weakness.
Blood: Bone-marrow stem cells lose balance, weakening immunity and reducing red blood cell production.
Brain: Fewer neural stem cells in the hippocampus affect memory and learning.
Liver and Pancreas: Their normally steady, low-level repair becomes even less adaptable, reducing resilience after illness or stress.
Interestingly, many tissues can briefly “rewind” cells to a younger, more flexible state after injury, a process known as cellular reprogramming [7]. However, with age, this plasticity fades, leaving fewer options for repair.
Can We Slow Down Stem Cell Exhaustion to Slow Ageing?
Scientists are exploring whether we can slow stem cell exhaustion - and ultimately slow ageing - by restoring some of the youthful power of our cells through a process known as cellular reprogramming [8]. This approach stems from the discovery of the Yamanaka factors, four genes that can “reset” a mature cell back to a flexible, pluripotent state, a breakthrough that earned Shinya Yamanaka the 2012 Nobel Prize.
However, full reprogramming can be dangerous in some cases as it can erase a cell’s identity and even trigger uncontrolled cell growth, therefore researchers are now testing partial or transient reprogramming, where these factors are switched on only briefly. This gentler approach gives ageing or damaged cells a rejuvenating push without turning them fully back into stem cells, and in pre-clinical studies it has shown promising effects on tissue repair in muscle, skin, and even the brain, with some models demonstrating restored memory function. While still experimental, this field offers an exciting glimpse of how we may one day not only slow ageing, but restore or replenish the stem cells that naturally decline over time.
Lifestyle Approaches to Keep Stem Cells in Check
Because stem cell exhaustion is influenced by many of the other hallmarks of ageing, no single remedy can preserve them forever. But everyday choices can make a meaningful difference:
1. Protect from damage
The simplest and most effective anti-ageing product is sunscreen. Shielding the skin from ultraviolet light prevents DNA damage and helps maintain healthy stem cells.
2. Support natural repair
Balanced nutrition, good hydration, and adequate sleep all support the body’s built-in renewal systems. Regular physical activity keeps muscle stem cells active and responsive.
3. Promote cellular clean-up
Short periods of fasting, or compounds such as spermidine, stimulate autophagy, the process where cells recycle damaged parts. This helps maintain stem cell function and energy balance.
4. Calm chronic inflammation
Persistent inflammation exhausts stem cells by keeping them constantly on alert. A diet rich in fruit, vegetables, and omega-3 fats, together with stress reduction and steady exercise, helps reduce this burden.
5. Avoid toxic overload
Smoking, excessive alcohol, and environmental pollutants all accelerate DNA and mitochondrial damage, wearing down stem cells prematurely.
Looking Ahead
Stem cell exhaustion represents the body’s declining capacity for self-renewal, a hallmark that ties together many other forms of cellular ageing. Yet research into reprogramming and rejuvenation shows that decline isn’t necessarily permanent. The same mechanisms that allow tissues to repair in youth can, in principle, be reignited later in life. Until those therapies arrive, supporting our stem cells through consistent lifestyle interventions remains the best strategy to maintain vitality.
References:
[1] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349
[2] Tian Z, Yu T, Liu J, Wang T, Higuchi A. Introduction to stem cells. Prog Mol Biol Transl Sci. 2023;199:3-32. doi: 10.1016/bs.pmbts.2023.02.012
[3] Alvarez CV, Garcia-Lavandeira M, Garcia-Rendueles ME, Diaz-Rodriguez E, Garcia-Rendueles AR, Perez-Romero S, Vila TV, Rodrigues JS, Lear PV, Bravo SB. Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells. J Mol Endocrinol. 2012 Aug 30;49(2):R89-111. doi: 10.1530/JME-12-0072
[4] Weissman IL, Anderson DJ, Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol. 2001;17:387-403. doi: 10.1146/annurev.cellbio.17.1.387
[5] Nardi NB. All the adult stem cells, where do they all come from? An external source for organ-specific stem cell pools. Med Hypotheses. 2005;64(4):811-7. doi: 10.1016/j.mehy.2004.08.026
[6] Rezazadeh S, Ellison-Hughes GM. Editorial: Stem cell exhaustion in aging. Front Aging. 2024 May 31;5:1433702. doi: 10.3389/fragi.2024.1433702
[7] Wang J, Sun S, Deng H. Chemical reprogramming for cell fate manipulation: Methods, applications, and perspectives. Cell Stem Cell. 2023 Sep 7;30(9):1130-1147. doi: 10.1016/j.stem.2023.08.001.
[8] Yücel, A.D., Gladyshev, V.N. The long and winding road of reprogramming-induced rejuvenation. Nat Commun 15, 1941 (2024). https://doi.org/10.1038/s41467-024-46020-5
[9] Liu X, Huang J, Chen T, Wang Y, Xin S, Li J, Pei G, Kang J. Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells. Cell Res. 2008 Dec;18(12):1177-89. doi: 10.1038/cr.2008.309
