Recent research has revealed that senescent cells, known as “zombie cells,” found in the skin can accelerate aging throughout the body, including the brain. When these cells were transplanted into animal models, they spread senescence to other organs, negatively affecting muscle and brain function. The discovery reinforces the importance of anti-aging strategies that address both skin health and overall body function by targeting these senescent cells.
Cellular senescence is a state in which cells permanently stop dividing due to various types of stress, such as aging or DNA damage.
These cells, also known as “zombie cells,” release a variety of inflammatory molecules known as SASP (Senescence-Associated Secretory Phenotype), which, while they may have positive functions such as helping with tissue repair or preventing cancer, can also cause problems if they persist in the body.
When present in excess, senescent cells and SASP can accelerate tissue aging and contribute to the onset of age-related diseases. Studies show that these cells accumulate in various tissues as we age.
Experiments in mice suggest that removing these cells can improve age-related functions, suggesting that cellular senescence plays a key role in the decline of bodily functions over time. One important question that researchers are still trying to understand is how these cells form and spread to different organs.
Senescent cells have been found to “infect” neighboring cells through chemical signals, such as SASP molecules, or through extracellular vesicles, spreading senescence from one tissue to another. This phenomenon can lead to systemic effects, where aging in one organ, such as the skin, can affect other distant organs.
As the largest organ in the body, the skin plays a critical role as a barrier against pathogens, chemicals, and UV radiation. During aging, the skin exhibits several structural, cellular, and molecular changes, including an accumulation of senescent cells that can be influenced by both intrinsic and extrinsic factors.
Interestingly, several studies propose skin aging as a potential predictor of age-related dysfunction in other organs. Some research has revealed correlations between skin aging and facial appearance with regard to longevity, susceptibility to disease, and mortality rates.
Furthermore, studies have indicated that exposure to ultraviolet radiation in mice can induce impaired hippocampal neurogenesis. This raises the intriguing concept that changes occurring in the skin can potentially manifest as changes in distal organs, notably including the brain.
These observations have led to the as-yet untested hypothesis that the accumulation of senescent cells within the skin may have the potential to spread senescence to other organs.
Researchers from the University of Coimbra and the Mayo Clinic tested the hypothesis that senescent cells in the skin could cause the aging of other organs, such as the brain.
They observed that the number of senescent cells in mice increases with age. To explore this, they transplanted senescent fibroblasts (a type of skin cell) into young mice and monitored the effects on other tissues.
The results showed that the presence of senescent cells in the skin can increase senescence in nearby and distant organs, leading to problems such as loss of muscle function and cognitive decline.
Brain analysis of these mice revealed a decline in cognitive functions, such as memory, related to the accumulation of senescent cells in the hippocampus, the area responsible for memory and learning. After the elimination of these cells, there was an improvement in cognitive function.
Finally, behavioral tests confirmed that mice with senescent cells transplanted into their skin showed a significant decline in spatial memory, although without clear signs of anxiety.
Intradermal transplantation of senescent cells induces cognitive decline in young mice. (a) 2–4 months after intradermal transplantation of proliferating or senescent fibroblasts, mice were assessed in a series of behavioral assessments, including the Y-maze and Stones maze tests, which assess spatial memory, as well as the elevated plus maze (EPM) and open field tests, which assess anxiety-like behavior. Using the Y-maze, mice were asked to remember which path was new. Mice with senescent cells took longer to explore the new path, suggesting memory impairments. The transplanted mice were assessed for (b) time spent in the novel arm and (c) latency to the novel arm. Using the Stones maze, we measured how many times the mice made mistakes while trying to exit the maze. Those with senescent cells made more mistakes, indicating a decrease in the ability to remember and navigate through space. The transplanted mice were assessed for (d) mean time to complete the test and (e) mean number of errors. (f) p21-, (g) IL1α-, and (h) Il6-positive cells in the CA3 region of the hippocampus.
These findings suggest that the accumulation of senescent cells in the skin may negatively affect other organs, especially the brain, potentially contributing to age-related cognitive decline.
These results open new perspectives on how treating skin aging may help mitigate systemic aging and associated diseases.
In addition, further research is needed to identify which factors released by senescent cells in the skin drive the systemic effects observed in host tissues. Such mechanistic studies may open new avenues for therapeutic intervention.
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Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline
Franco AC, et al.
Aging cell. 07 October 2024. https://doi.org/10.1111/acel.14340
Abstract:
Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.
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