How Aging Cells Help or Hinder Healing
Aging cells, called senescent cells, have a surprising double life when it comes to healing - some help repair wounds while others slow the process down.
STORY AT-A-GLANCE
Senescent cells, which have stopped dividing, have a complex role in wound healing; some types are beneficial while others hinder the process
Certain senescent cells, particularly those high in p21, hinder wound healing by promoting inflammation, unlike helpful p16-high cells
In chronic wounds, a persistent accumulation of harmful senescent cells disrupts the normal healing process, leading to delayed closure and fibrosis
Natural senolytic compounds, such as fisetin and quercetin, found in various fruits and vegetables, offer a way to clear harmful senescent cells
A healthy lifestyle, including reducing your intake of polyunsaturated fats like linoleic acid, helps minimize cellular damage and promote a healthy balance of senescent cells
Have you ever noticed that a small cut or scrape seems to take longer to heal as you get older? This common experience is linked to changes happening at the cellular level, specifically with cells called senescent cells. These cells have stopped dividing, essentially "retiring," but they don't simply disappear.
For a long time, scientists believed these retired cells were mostly harmful, contributing to the aging process and various diseases. However, new research is revealing a more complex story: some senescent cells are actually beneficial for wound healing, while others hinder it.
What Are Senescent Cells, and Why Do We Have Them?
Your body is made up of trillions of cells that constantly divide and replace old or damaged ones. This process of cell division is necessary for growth, repair and overall health. However, cells don't divide infinitely. There's a limit, often called the Hayflick limit, to the number of times a cell divides. When a cell reaches this limit, or if it experiences significant damage, it enters a state called cellular senescence.
These senescent cells don't die, but they stop dividing. Think of them like retired workers. They're no longer actively producing, but they still influence their environment. Initially, scientists viewed senescent cells as primarily detrimental. They were linked to inflammation and various age-related diseases.
This negative view stemmed from the fact that senescent cells release a cocktail of signaling molecules known as the senescence-associated secretory phenotype, or SASP. The SASP is like a neighborhood's communication network. Some messages are helpful, like warnings of danger, while others are less helpful, like gossip. Similarly, some SASP factors promote tissue repair, while others can trigger harmful inflammation.
Several factors cause a cell to become senescent. These triggers include damage to DNA, stress from harmful molecules called free radicals (oxidative stress) and the activation of genes that promote cell growth (oncogenes). Certain proteins, like p21 and p16, play important roles in initiating and maintaining this state of senescence.1 These triggers are like different reasons why someone might retire early. It could be due to an injury, burnout or simply reaching a certain age.
The accumulation of senescent cells is closely linked to the aging process. As you age, more and more of these cells build up in your tissues, contributing to decline in organ function and increasing the risk of age-related diseases. This understanding of senescence as a primarily negative process set the stage for new research that revealed a surprising twist: the dual role of these cells in wound healing.
The Complex Role of Senescent Cells in Wound Repair
While often associated with aging and disease, senescent cells have a complex role in your body, especially when it comes to wound healing. Not all senescent cells are the same. For instance, they may be categorized based on the expression of different proteins, such as p16 and p21. Research conducted at the University of Connecticut focused on the distinct roles of p16-high and p21-high senescent cells in skin wound healing.2
Previous studies had indicated that p16-high cells played a positive role in this process. However, the role of p21-high cells was largely unknown. The researchers conducted experiments on mice, selectively removing p21-high senescent cells. They found that removing p21-high cells accelerated wound closure in female mice by about 25%.3 This discovery revealed that p21-high senescent cells, unlike p16-high cells, have a detrimental effect on wound healing.
Further investigation revealed that p21-high cells tend to originate from connective tissue, skin and the immune system, and have a proinflammatory profile, suggesting that their negative impact on healing may be related to excessive inflammation.4 These results highlight the importance of distinguishing between different types of senescent cells when studying their effects on wound healing and other biological processes.
The Negative Impact of Persistent Senescence
While some senescent cells contribute to early wound repair, others hinder healing, particularly in chronic wounds, which fail to heal within a normal timeframe. These types of wounds are a common problem for people with diabetes and older adults.5
The accumulation of certain types of senescent cells contribute to delayed wound healing in chronic wounds.6 These cells cause persistent inflammation and impair the regeneration of new tissue, preventing the wound from closing properly.
The SASP also plays a role in this negative aspect of senescence. Certain SASP factors promote ongoing inflammation, block cell growth and break down the extracellular matrix. This breakdown is counterproductive for proper wound closure. In this context, the SASP actively disrupts the healing process rather than promoting it.
While senescent cells play a helpful role in the initial stages of wound healing, their presence over the long term creates significant problems. Think of wound healing as a carefully orchestrated construction project. In the early phases, senescent cells act like skilled project managers, coordinating the arrival of different work crews (other cells) and ensuring that the initial repairs are carried out efficiently.
They do this by releasing signaling molecules — the SASP — which are like instructions and communication between the different teams. However, if these project managers stick around for too long, their instructions become outdated or even counterproductive, hindering the later stages of construction. This is what happens in chronic wounds.
As noted in a review published in Frontiers in Immunology,7 in normal, acute wounds, senescent cells appear briefly and then are cleared away by your body's immune system as the wound heals. This allows the construction project to progress smoothly to the later phases of rebuilding and remodeling the tissue.
However, in chronic wounds, these senescent cells persist, constantly releasing the SASP signals. This continuous signaling leads to a state of chronic inflammation, which disrupts the normal healing process. This chronic inflammation prevents new, healthy tissue from forming properly and even leads to the breakdown of existing tissue. The signals from the SASP also stimulate cells called fibroblasts to produce excessive amounts of collagen, a key component of scar tissue.
This overproduction of collagen leads to fibrosis, which further impedes healing and causes discomfort. The study also highlights how age-related changes, like decreased collagen production and a weaker immune system, worsen these negative effects in older individuals.
Senolytics Target Senescent Cells
Scientists are actively exploring ways to target senescent cells in chronic wounds and other areas of the body. One approach involves using drugs called senolytics. These drugs act like a targeted demolition crew, selectively eliminating the problematic senescent cells.
Another approach focuses on using senomorphics, which act more like a management consultant, modifying the signals released by senescent cells (the SASP) to reduce their harmful effects without killing the cells themselves.
While the featured study suggests not all senescent cells are harmful, other research has found that natural senolytic compounds like fisetin may extend mortality in certain cases, such as in those with COVID-19, by reducing the burden of senescent cells.8
Fisetin, a flavonoid, is found in fruits and vegetables, particularly strawberries and apples. While it may be difficult to get a therapeutic amount from food alone, adding fisetin-containing foods to your diet is one way to promote a healthy balance of senescent cells. Quercetin also acts as a senolytic agent, including against senescence-mediated cancer growth.9
Quercetin is found in many foods, including citrus fruits, green leafy vegetables, broccoli, apples, onions, green tea, red grapes, dark cherries and berries, such as blueberries and cranberries. Among these, the highest levels are found in apples — especially the skins — onions, broccoli, cherries, berries and green tea.
For an especially concentrated source, consider onion skins. They may have 77 times more quercetin than the flesh.10 While consuming onion skins may be unpalatable, consider sipping on a broth made from onion peels for more potent therapeutic effects.
Quercetin is also found in medicinal products such as Ginkgo biloba, St. John's Wort (Hypericum perforatum) and elderberry (Sambucus canadensis). If you're using quercetin in supplement form, consider taking it at night (with zinc) before you go to bed and you haven't eaten for at least three to four hours to optimize its senolytic properties.
Balancing the Effects of Aging Cells for Better Healing
The research on senescent cells has revealed a complex picture. These "retired" cells play a dual role in wound healing and likely other biological functions. Some types of senescent cells help kickstart the healing process, while others can prolong it, especially in chronic wounds.
The key takeaway is that the context and timing of senescent cell activity are important. Understanding this balance is essential for developing effective therapies and reducing premature aging. This new understanding of senescent cells also opens up possibilities for improving wound healing, particularly in older adults who often experience delayed healing.
By targeting certain senescent cells, scientists hope to promote faster and more complete wound closure. Maintaining a healthy lifestyle is also important for minimizing cellular damage and promoting healthy aging. A balanced diet, regular exercise and stress management all contribute to reducing the accumulation of harmful senescent cells.
In addition, increased fat oxidation disrupts cellular metabolism, leading to accelerated aging and the development of age-related diseases. When your body shifts from burning glucose to burning fats, it creates an imbalance that results in reductive stress and the buildup of harmful molecules like reactive oxygen species.
This metabolic shift interferes with cellular functions, pushing cells into a state of senescence. Reducing your intake of linoleic acid (LA), a common polyunsaturated fatty acid found in many seed oils, will help maintain metabolic balance and prevent cellular damage.
The key way to do this is by avoiding processed foods, most of which contain seed oils. While research in this field is ongoing, staying informed about the latest discoveries empowers you to make informed choices about your health.
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