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What role does gut microbiota play in healthy aging?
Aging, defined as the progressive decline in physiological function and cellular integrity over time, is accompanied by an increased susceptibility to various diseases, including cancer, obesity, and neurodegenerative disorders like Alzheimer’s disease. As life expectancy rises globally, ensuring healthy aging has become an urgent concern. The aim is to maintain physical and cognitive function, independence, and overall quality of life among the older population.
In older individuals, the gut microbiota often experiences significant alterations in composition and function in comparison to that of younger adults. These changes include a decline in beneficial commensal bacteria, such as Bifidobacterium and Lactobacillus species, and an increase in potentially pathogenic microorganisms or pathobionts like Proteobacteria. This imbalance, known as dysbiosis, is exacerbated by age-related changes in immune function and gut barrier integrity, leading to chronic low-grade inflammation, a hallmark of aging. Moreover, due to dysbiosis, there is a reduction in the release of short-chain fatty acids (SCFAs), which possess anti-inflammatory properties. Consequently, disruptions in key metabolic processes occur, exacerbating inflammation, oxidative stress, and tissue damage, thereby contributing to the pathogenesis and progression of age-related diseases.
In addition to dysbiosis, the uniqueness of the gut microbiota plays a pivotal role in healthy aging, as individual variations in microbial composition and function influence the process. Therefore, the study of the gut microbiota in centenarians poses unique challenges due to their small population size worldwide, making it difficult to achieve uniformity in study samples. Despite these challenges, studies on centenarians have revealed intriguing microbial signatures associated with longevity. For instance, in the study of Hainan centenarians, it became clear that the gut microbiomes of healthy aging male and female centenarians exhibit sex dependent differences. Thus, there may be a sex-specific role of the microbiome in healthy aging. Fecal microbiota composition correlates with residential location and diet among older individuals. Most centenarians are found in the “blue zone” areas characterized by a healthy lifestyle, including dietary patterns, exercise habits, and social engagement, which likely play a part in maintaining a resilient gut microbiota, contributing to their remarkable longevity and vitality. Interestingly, individuals in regions like Japan, Italy, Costa Rica, and Greece share similar dietary habits, emphasizing a predominantly plant-based diet abundant in vegetables, fruits, whole grains, legumes, and nuts, with moderate consumption of red meat and regular intake of antioxidant-rich foods such as olive oil, herbs, and spices.
What is the importance of inflammation control via the gut microbiota in healthy aging?
Inflammation, often termed “inflammaging” in the context of aging, is a pivotal factor in the pathogenesis of numerous age-related diseases. Chronic low-grade inflammation, characterized by sustained elevation of pro-inflammatory cytokines and immune activation, contributes to the onset and progression of various conditions associated with aging. Interestingly, gut microbiota dysbiosis can result in increased intestinal permeability, allowing bacterial products such as lipopolysaccharides (LPS) to enter the bloodstream and trigger immune responses, leading to systemic inflammation.
In older individuals, inflammation and alterations in the gut microbiota have profound implications for a range of age-related diseases. In arthritis and osteoporosis, dysbiosis of the gut microbiota can exacerbate inflammation and contribute to joint degradation and bone loss. Similarly, in diabetes and cancer, gut microbiota imbalances can induce chronic inflammation, insulin resistance, and tumor progression. Furthermore, susceptibility to infectious diseases increases with age, partly due to alterations in gut microbial composition and immune function. Understanding the interplay between inflammation, the gut microbiota, and these diseases is crucial for developing targeted interventions to improve health outcomes in the older population.
Specifically focusing on the three most prevalent diseases in older individuals, sarcopenia, neurodegenerative diseases such as Alzheimer, and cardiovascular disease (CVD):
Sarcopenia, characterized by progressive loss of muscle mass, strength, and function, is a prevalent condition among aging populations worldwide. Inflammation can dysregulate muscle protein synthesis by promoting muscle protein breakdown and inhibiting protein synthesis. Additionally, alterations in the gut microbiota composition can impair nutrient absorption, including essential amino acids and vitamins crucial for muscle health. Dysbiosis-induced alterations in SCFAs production can disrupt energy homeostasis, further exacerbating muscle loss in sarcopenia.
Alzheimer’s disease is closely associated with neuroinflammation in the brain. Recent findings suggest that gut dysbiosis may play a role in neuroinflammation and cognitive impairment. Specifically, dysbiosis-induced disturbances in the gut-brain axis can increase the permeability of the blood-brain barrier. This increased permeability may allow microbial metabolites and pro-inflammatory molecules to enter the brain, triggering neuroinflammation and accelerating cognitive decline in aging individuals.
Similarly, inflammation plays a central role in the development and progression of cardiovascular diseases (CVD), including atherosclerosis, myocardial infarction, and stroke. Endothelial dysfunction, characterized by impaired vascular homeostasis and increased expression of adhesion molecules and pro-inflammatory cytokines, contributes to the initiation and propagation of atherosclerotic lesions. Dysbiosis-mediated alterations in microbial metabolites, such as trimethylamine N-oxide (TMAO), derived from protein fermentation, promote vascular inflammation and atherogenesis, leading to cardiovascular events.
What are the possible gut microbiome-targeted interventions?
Interventions targeting the gut microbiome offer promising avenues for promoting healthy aging, but each comes with its own set of considerations.
- Dietary interventions, such as the Mediterranean diet or high-fiber diets, offer the advantage of being easily accessible and customizable to individual preferences, with broad health benefits extending beyond the gut microbiome. However, following such a diet is only feasible for a small percentage of population for reasons of time and resources, and the effects may vary depending on adherence to the diet and the baseline composition of the microbiome.
- Probiotics provide a convenient option with various formulations available, but their efficacy can vary widely depending on strain, dose, and individual microbiome composition, with potential for adverse effects in immunocompromised individuals. Some studies have shown that certain strains of Bifidobacterium and Lactobacilli can promote the production of anti-inflammatory cytokines, reduce C-reactive protein levels, enhance cognitive function, decrease bone loss, while increasing the release of SCFAs.
- Prebiotics serve as substrates for beneficial bacteria and can be included in a variety of foods and supplements, but their effects vary widely from one individual to another, and high doses may lead to gastrointestinal discomfort. For instance, while inulin is commonly used, it may not effectively induce measurable changes to improve healthy aging, despite notably increasing the release of SCFAs.
- Postbiotics offer the advantage of providing beneficial effects without live microorganisms, but there is limited understanding of mechanisms and optimal dosing, as well as variability in bioavailability and efficacy.
- Fecal microbiota transplantation (FMT): FDA approved two microbiome-based therapies for the prevention of a recurrence of Clostridioides difficile infection, which is common in older individuals, especially those hospitalized. Fecal microbiota products also show promise for other diseases associated with dysbiosis, such as inflammatory bowel diseases (IBD) and metabolic syndromes. Despite this milestone, challenges remain, including the need for long-term safety data, potential risks of pathogen transmission, and ethical considerations.
Moreover, the integration of AI and machine learning technologies holds promise for advancing personalized interventions by analyzing vast datasets to predict individual responses to different microbiome interventions. As research progresses and our understanding of the gut microbiome deepens, these innovative approaches may complement traditional interventions, offering new opportunities for promoting gut health and addressing age-related diseases in the older populations. However, the current challenge also lies in addressing public health nutrition and the lack of education in nutrition among the general population. Efforts to improve access to healthy dietary options are essential for maximizing the effectiveness of gut microbiome interventions and promoting healthy aging on a population scale.
Take home messages:
- The gut microbiota profoundly influences health and disease as we age, with dysbiosis associated with inflammation and susceptibility to age-related conditions.
- Chronic low-grade inflammation, termed “inflammaging,” is a key factor in age-related diseases. Controlling inflammation through gut microbiota interventions emerges as a potential tool for healthy aging.
- Dietary changes, probiotics, prebiotics, postbiotics, and fecal microbiota transplantation (FMT) offer potential ways to modulate the gut microbiota and promote healthy aging.
- Integrating AI and machine learning can enhance personalized interventions, while improving public health nutrition is vital for maximizing the impact of gut microbiota interventions on healthy aging.
References:
Ghosh, T.S., Shanahan, F. & O’Toole, P.W. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol (2022). https://doi.org/10.1038/s41575-022-00605-x
Ragonnaud, E., & Biragyn, A. (2021). Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun. Ageing, 18(1), 2. https://doi.org/10.1186/s12979-020-00205-8
Dissanayaka DMS, Jayasena V, Rainey-Smith SR, Martins RN, Fernando WMADB. (2024). The Role of Diet and Gut Microbiota in Alzheimer’s Disease. Nutrients. 16(3),412. https://pubmed.ncbi.nlm.nih.gov/38337696/
Chulenbayeva L, Ganzhula Y, Kozhakhmetov S, Jarmukhanov Z, Nurgaziyev M, Nurgozhina A, Muhanbetzhanov N, Sergazy S, Zhetkenev S, Borykbay Z, Tkachev V, Urazova S, Vinogradova E, Kushugulova A. (2024). The Trajectory of Successful Aging: Insights from Metagenome and Cytokine Profiling. Gerontology. https://pubmed.ncbi.nlm.nih.gov/38246133/
Luan Z, Fu S, Qi S, Li C, Chen J, Zhao Y, Zhang H, Wu J, Zhao Z, Zhang J, Chen Y, Zhang W, Jing Y, Wang S, Sun G. (2024) A metagenomics study reveals the gut microbiome as a sex-specific modulator of healthy aging in Hainan centenarians. Exp Gerontol. 186,112356. https://doi.org/10.1016/j.exger.2023.112356
Claesson, M., Jeffery, I., Conde, S. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012). https://doi.org/10.1038/nature11319
Lyu, Z., Hu, Y., Guo, Y. et al. Modulation of bone remodeling by the gut microbiota: a new therapy for osteoporosis. Bone Res 11, 31 (2023). https://doi.org/10.1038/s41413-023-00264-x
Ticinesi A, Nouvenne A, Cerundolo N, Parise A, Mena P, Meschi T. (2024) The interaction between Mediterranean diet and intestinal microbiome: relevance for preventive strategies against frailty in older individuals. Aging Clin Exp Res. 36(1):58. doi: 10.1007/s40520-024-02707-9
Carloni S, Rescigno M. The gut-brain vascular axis in neuroinflammation. Semin Immunol. 2023;69:101802. doi:10.1016/j.smim.2023.101802.
Mullard A. (2023) FDA approves second microbiome-based C. difficile therapy. Nature Reviews Drug Discovery. https://www.nature.com/articles/d41573-023-00081-1#:~:text=The%20FDA%20has%20approved%20Seres,difficile%20infection%20following%20antibiotic%20treatment.
Tkach S, Dorofeyev A, Kuzenko I, Boyko N, Falalyeyeva T, Boccuto L, Scarpellini E, Kobyliak N, Abenavoli L. (2022) Current Status and Future Therapeutic Options for Fecal Microbiota Transplantation. Medicina (Kaunas). 58(1):84. doi: 10.3390/medicina58010084.
Gibbons SM, Gurry T, Lampe JW, Chakrabarti A, Dam V, Everard A, Goas A, Gross G, Kleerebezem M, Lane J, Maukonen J, Penna ALB, Pot B, Valdes AM, Walton G, Weiss A, Zanzer YC, Venlet NV, Miani M. (2022) Perspective: Leveraging the Gut Microbiota to Predict Personalized Responses to Dietary, Prebiotic, and Probiotic Interventions. Adv Nutr. 13(5):1450-1461. doi: 10.1093/advances/nmac075.
