October 2024 Issue
Cracking the Code to Cell Senescence
By Sherry Coleman Collins, MS, RDN, LD
Today’s Dietitian
Vol. 26 No. 8 P. 22
Can Manipulating the Microbiome Slow the Aging Process?
In 1961, researchers Leonard Hayflick, PhD, and Paul Moorhead, PhD, observed that human cells could only divide a limited number of times before they became unable to continue to do so.1 Further research found that sometimes these cells don’t die and are not cleared by the immune system. The discovery of this cell cycle arrest phenomenon, deemed “cellular senescence,” led to a great deal of study on the topic in the decades that followed as researchers sought to understand how and why cells stop reproducing and the impact of cell damage and stress.2
Cells in a state of senescence may accumulate in the body as we age; they secrete inflammatory modulators that can cause harm to neighboring cells.2 Researchers suspect the buildup of these cells may influence age-related and immune-mediated disease conditions such as cancer, diabetes, osteoporosis and osteoarthritis, CVD, stroke, autoimmune conditions, neurodegenerative diseases, and dementias, including Alzheimer’s disease.2,3
Complicating things a bit more, cell senescence has been associated with both negative and positive effects on human health, including both tumor suppression and promotion.1
Emerging and Evolving Research
To better understand cellular senescence and its impact on human health, the National Institutes of Health created the Cellular Senescence Network (SenNet) for collaboration between the National Institute on Aging and the National Cancer Institute. Research into the potential for clearing senescent cells from the body is underway but is limited and still in the early stages. In very small studies, researchers have found positive results clearing senescent cells using a combination of the chemotherapy drug dasatinib with the flavonoid quercetin in mouse models and human trials to treat lung disease and diabetic kidney disease.2 The class of medications dedicated to the goal of clearing senescent cells is called senolytics.
In one study, researchers exposed healthy young mice to senescent cells and observed age-related declines in the specimens, further confirming the impact of senescent cells.2 Others are studying ways to reduce the harmful chemicals secreted by senescent cells, potentially reducing or eliminating their negative impacts.2
The Microbiome and Cell Senescence
It’s well known that the gut microbiome changes over time. During a vaginal birth, babies inherit their original microbiome from their mothers, being composed of vaginal and gastrointestinal bacteria, while babies born via cesarean section have a microbiome more like the skin.4 Over time, the composition of the infant microbiome changes in response to breastmilk or formula, pets in the home, number of siblings, and much more. In fact, throughout the lifecycle, the gut microbiome is impacted by many factors including diet (ie, fiber consumption), medications (ie, antibiotics), stress, and illness, among others. These influences have an impact throughout the lifespan into older age.4
In a 2020 systematic review of 27 studies exploring the relationship between the microbiome and healthy aging published in Nutrients, the authors suggest that the microbiome plays a strong role in longevity, including normal and successful aging, across species. This is in part due to its ability to modulate immune response, including pro- and anti-inflammatory activity.5 Immune system dysregulation may drive proinflammatory states and impact cell signaling.5
According to Rohit Sharma, PhD, an assistant professor at the Nutrigerontology Laboratory at Shoolini University, “Chemicals such as trimethylamine N-oxide (TMAO) produced by the gut bacteria are known to accelerate inflammation and aging.” In addition, mouse models have shown that some bacteria, including Lactobacillus fermentum, secrete beneficial metabolites that help prevent cell senescence.6
In an interview, Sharma explains that the gut microbiota is in close proximity to the epithelial cells of the gut allowing for bidirectional communication between host cells and the bacteria. While the microbiota do not cross the gastrointestinal barrier in healthy individuals, there is nonetheless a transfer of metabolites such as TMAO which can have an influence on organ systems and cells far from the gut. Knowing this, current themes of research include considering how to positively impact the balance of beneficial bacteria and microbial diversity while reducing the numbers of potentially harmful, inflammation-promoting ones as humans age. There is still much to learn about the role of cell senescence in human health and how manipulating these microbial cells may impact overall health and longevity, including the role of diet and nutrition.
Calorie Restriction and Cell Senescence
Researchers have known for decades that certain types of calorie restriction in mammals may increase longevity.7 In the 1980s and 1990s, researchers discovered genes associated with longevity, followed by research in the 2000s that revealed these genes were activated by calorie restriction. Since then, additional research has shown that calorie restriction impacts cell senescence, building on previous research to help explain the mechanism for increased longevity through very low-calorie diets.8 In animal studies that look to extend longevity, the degree of calorie restriction has at times been quite severe and may not have practical relevance in the human setting for a variety of reasons, including questions of safety. It’s also unclear what the longer-term physiological impacts may be for different degrees of restriction, including in humans.
A novel case study was published in 2022 where the gut microbiota of an overweight female woman was transplanted into mouse models before and after the woman consumed an eight-week very low-calorie diet of only 800 kcal per day.9 In the mice who received the microbiota transplant following the restrictive diet, there was a significant shift in the microbiota with an increase in beneficial bacteria and diversity. A reduction in body fat accumulation and improved blood glucose tolerance were also observed in this group, as well as positive changes in the immune cells compared with those who received the transplant before the restrictive diet.9 These results suggest a need for more research on microbiota transplantation as a potential mechanism to help repair dysfunctional metabolism. However, this was a very small study, and more research is needed before broader conclusions can be made.
Eating for Healthy Aging: Practical Recommendations
Cell senescence can be influenced by stress and cell damage, making nutrition a powerful potential modulator of this process. Nutritional stressors in the form of nutrient imbalances and consumption of a diet high in proinflammatory factors driving more oxidative stress may negatively impact cellular health. On the other hand, a diet replete with appropriate amounts of macro- and micronutrients, fiber, and phytonutrients, as well as probiotics, may protect cells.5
According to Maggie Moon, MS, RD, and Los Angeles-based brain health dietitian and author of Telomere Diet & Cookbook and The MIND Diet: 2nd Edition, “Since animal studies show oxidative stress leads to more cellular senescence, eating a greater variety of plant foods, especially fermented foods, to reduce oxidative stress and inflammation is a good place to start.” Moon says to look for polyphenol-rich foods that contain natural senolytics like quercetin, commonly found in apples and onions, and resveratrol, which is found in grapes, peanuts, cocoa, and berries, to improve microbiome diversity.
Multiple components of the diet impact the microbiome and, by extension it seems, cell senescence. Carbohydrates are a broad category of macronutrient and are an important source of energy for cells, including good bacteria.10 Complex carbohydrates, such as whole and intact grains, fruits and vegetables, and beans, provide dietary fiber, which serves as fuel for beneficial microbiota and should be encouraged for individual tolerance.
Specific types of fatty acids can have an impact on the microbiome, as well as the total amount of fat eaten.3,10 Diets very high in saturated fat have been shown to have a negative impact on microbial diversity.10 Conversely, omega-3 fatty acids have been associated with improved immune function, and polyunsaturated fatty acids may encourage the growth of beneficial bacteria.10 Eating enough vitamin and mineral-rich foods is important, and there have been specific benefits connected to adequacy in vitamins D, E, B2, and the mineral zinc for mitigating cell senescence, according to a review by Diwan and Sharma published in Food Science Biotechnology.3 The review also lists polyphenols, including green tea ECGC, berberine, resveratrol, quercetin, kaempferol, tocotrienol, genistein, pterostilbene, and apigenin as having potential protection against the impacts of cell senescence, but more research is needed.3
Probiotics and prebiotics from food or supplements are also a way to help modify the gut microbiome. Certain types of bacteria are associated with fewer senescent cells, and researchers are exploring a role for targeted probiotic or prebiotic supplementation in the future. In the absence of specific clinical recommendations, including dosing, Sharma recommends including probiotic and probiotic fermented foods in the diet daily. According to emerging evidence, he says, encouraging this microbial balance and diversity may help the body improve multiple facets of metabolism, including immunoregulation and maintenance of inflammatory homeostasis, that could ultimately help delay the onset of stress-induced cell senescence.
An overall diverse diet that meets nutrient needs; leans heavily on whole, colorful, fiber-rich plant-based foods; and includes healthful omega-3 fats along with some fermented foods is a good dietary pattern starting point for most people and seems to encompass most of what the research on cell senescence and aging supports so far. Yet, determining a diet that meets the needs of the individual, including age, health status, and individual tolerance and tastes, can be complex. It’s important that recommendations consider personal preferences, be culturally appropriate, and take into account socioeconomic factors. In an older population, consideration for chewing and swallowing functionality is also important.
Key Takeaways and Looking Forward
While the research in this area is very exciting, there’s still a lot we don’t yet know. According to Sharma, “We need plenty of research to assess the scope and impact of this [microbiome and cell senescence] hypothesis.” For instance, he says, we do not yet know which metabolites of the gut metabolome are involved in accelerating the senescence or the underlying mechanisms. There is also a lack of research about whether and how senescent cells of the gut can impact gut microbiota composition and diversity, particularly as humans age.
Moon says, “It would be helpful to conclusively know that dietary approaches to addressing gut dysbiosis can reduce senescent cell accumulation and their harmful secretions in humans. So much of the current research is in vitro, in cell lines or in animals.” That’s a big deal because, while it’s helpful to have preliminary research of this nature, these studies do not always translate to free-living—and eating—humans.
“As the research evolves, dietitians will be essential in translating study findings into practical snacks and meals,” Moon says. She says RDs may also find opportunities to work in clinical trials to help better understand this area and in research and development roles for companies looking to create products to meet consumer interest.
Trends in aging and nutrition marketing for older Americans predict there will be plenty of interest. Current estimates are that the number of Americans 65 years and older is expected to reach 71 million in 2030, including 19.5 million over 80 years old.11 Aging Americans want to live healthier as they live longer. Moreover, there is huge interest in gut health, with a related market valued at more than $51 billion in 2023.12 Supporting the microbiome and managing the impact of cell senescence could be a food and nutrition trend that is ripe to make a big difference in public health.
Interested RDs should keep an eye on the research in this area since there is strong potential that dietary manipulation could be a primary way to help reduce cell senescence, according to the research so far. Sharma says, “Through my research and experience, I believe that the gut microbiota is likely to emerge as one of the most direct external influencers of organismal aging. The future of aging research has to pass through the ‘gut.’”
— Sherry Coleman Collins, MS, RDN, LD, is president of Southern Fried Nutrition Services in Atlanta, specializing in food allergies, digestive wellness, and nutrition communications. Follow her on X, formerly known as Twitter; Instagram; and Facebook @DietitianSherry.
References
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2. Does cellular senescence hold secrets for healthier aging? National Institute on Aging website. https://www.nia.nih.gov/news/does-cellular-senescence-hold-secrets-healthier-aging. Published July 13, 2021. Accessed July 10, 2024.
3. Diwan B, Sharma R. Nutritional components as mitigators of cellular senescence in organismal aging: a comprehensive review. Food Sci Biotechnol. 2022;31(9):1089-1109.
4. Wernroth ML, Peura S, Hedman AM, et al. Development of gut microbiota during the first 2 years of life. Sci Rep. 2022;12(1):9080.
5. Badal VD, Vaccariello ED, Murra ER, et al. The gut microbiome, aging, and longevity: a systematic review. Nutrients. 2020;12(12):3759.
6. Kumar R, Sharma A, Gupta M, Padwad Y, Sharma R. Cell-free culture supernatant of probiotic lactobacillus fermentum protect against H2O2 induced premature senescence by suppressing ROS-Akt-mTOR Axis in Murine Preadipocytes. Probiotics Antimicrob Proteins. 2020;12(2):563-576.
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8. Longo V, Cortellino S. Fasting, dietary restriction, and immunosenescence. J Allergy Clin Immunol. 2020;146(5):1002-1004.
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10. Tamayo M, Olivares M, Ruas-Madiedo P, et al. How diet and lifestyle can fine-tune gut microbiomes for healthy aging. Ann Rev Food Sci Technol. 2024;15:283-305.
11. Public health and aging: trends in aging --- United States and worldwide. MMWR. 2003;52(06):101-106.
12. Digestive health products market trends. Grand View Research website. https://www.grandviewresearch.com/industry-analysis/digestive-health-products-market. Accessed July 21, 2024.