Healthy Aging and the Microbiome

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    The world’s population is aging rapidly, bringing extreme burdens to public healthcare systems. Frailty and premature death affect many elderly people, but not all. People age differently.  

    FYI: Frailty has been defined asa state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes, including falls, delirium, and disability.” 

    The highly complex aging process is marked by various biological actions, which can be affected by genetic background and lifestyle, among other factors.  

    Now, a growing body of evidence links the aging process to the gut microbiome. Given its widespread impact on health, the gut microbiome may offer clues to variable aging along with potential solutions to extend a healthy lifespan. 

    Gut microbiome and aging, in brief 

    Over a century ago, Elie Metchnikoff hypothesized that health could be enhanced and senility delayed by manipulating the intestinal microbiome with host-friendly bacteria found in yogurt (The Prolongation of Life: Optimistic Studies, 1907). His pioneering work laid the foundation for the field of probiotics as well as gerontology. 

    More recent research shows that aging results in a decline in diversity and homeostasis of gut microbiomes, and their changes are related to adverse health outcomes. Also, many common issues in older people, such as exposure to multiple drugs, dietary changes and physical inactivity, are closely correlated with perturbations in gut microbiome composition and function (dysbiosis). It is not clear whether microbiota alterations are a cause or consequence of aging. This important distinction will inform a role for microbiome modulation in aging, or not. 

    As people age, they are more susceptible to both chronic and infectious diseases. However, there are exceptions to this, as seen with healthy centenarians 

    Gut microbiota in healthy elderly 

    Scientists have looked at different groups of centenarians (100+ years of age) to see if their gut microbiomes were unique.  

    In one example, in a small group of centenarians in Italy, Akkermansia muciniphila (A. muciniphila) as well as Bifidobacterium and Christensenellaceae were enriched. 

    Elsewhere, in a group of Japanese centenarians (average age 107), distinct compositions enriched in microorganisms that produce bile acids with antimicrobial properties were observed. 

    Many more studies highlighted that people who reach 100+ years of age in relatively good health appear to host gut microbiota with more diversity and increased beneficial organism content.  

    Gut dysbiosis and frailty 

    Changes in the gut microbiome in the elderly may modulate the immune system, driving chronic inflammation or what is called “inflammaging”—a factor in frailty and poor health.  

    Dysbiosis of aged gut microbiota is linked to aberrations of gut barrier integrity and enhanced pro-inflammatory cytokines. These changes may underlie the pathogenesis and progression of various metabolic diseases that are prevalent in old people such as obesity, insulin resistance, fatty liver, and cardiovascular diseases. The gut-brain axis can also be impacted by the aging microbiome, leading to various neurological diseases. 

    A pathway is clearly stated in a 2021 review: 

    “Frail elderly people show increased gut dysbiosis, a severe decrease of beneficial commensal bacteria, such as Akkermansia muciniphila and SCFA-producing bacteria, and a marked increase of opportunistic and potentially proinflammatory commensal microbes. It leads to impairment of the intestinal epithelial integrity and increases gut leakiness and translocation of opportunistic bacteria and endotoxin into the circulation, causing a chain of inflammatory events that enhance the risk of developing aging-associated pathologies.” 

    Thus, gut microbiota may be associated with inflammaging and age-related chronic health conditions, making it a target for novel treatments to improve the aging process.  

    Altering the gut microbiota for healthier aging 

    Mechanisms 

    A deteriorating immune system (immunosenescence) and inflammaging are characteristic of aging and contribute to age-related disorders.  

    Studies in both experimental animals and human subjects have shown that probiotic bacteria can alter some of the deleterious aspects of immunosenescence. On the other hand, the study of probiotic modulation of cell senescence is limited. However, animal studies suggest that probiotics can influence the progression and severity of cell senescence. 

    Probiotic organisms may have positive effects through many probable mechanisms: Increased antioxidant activity, regulation of lipid deposits and metabolism, reduced insulin resistance, improvement of mucosal barriers, enhanced immune function, and elevation of short-chain fatty acids (SCFAs).  

    Modulations 

    Animals 

    Probiotic supplementation has shown promising results in improving the longevity of experimental animals 

    Strains of various probiotic species including Ligilactobacillus salivarius, Lacticaseibacillus rhamnosus, Bacillus licheniformis,Lactobacillus gasseri, and Limosilactobacillus fermentum extended the lifespan of Caenorhabditis elegans, a nematode acknowledged in recent decades as an interesting model system for  studies  on aging and age related diseases.   

    In many studies using rodent models, various probiotic treatments improved learning, memory, and/or other markers of healthy aging. 

    Like short-chain fatty acids (SCFAs), polyamines are produced by commensal bacteria and play critical roles in cell processes. Both decline with age. Supplementation of probiotic bacteria that produce polyamines has shown lifespan-enhancing effects in mice.  

    Humans 

    Obviously, humans are not rats or nematodes. Whether probiotics may or already are extending lifespan will be difficult to discern in our own species. But, extending healthy years in old age through probiotic treatment is already a reality. The anti-inflammaging, antioxidant, and anti-immunosenescence effects of probiotics suggest their potential in modulating senescence (biological aging of cells or whole organism), especially oxidative stress-induced senescence. 

    Probiotics are already being deployed to improve elderly health in treating infections, diarrhea, and inflammatory disorders among others. New evidence suggests that probiotics may be able to do more to enhance healthy aging.  

    Over the past two decades, numerous randomized clinical trials have been conducted in various target populations, including older adults, to investigate the effectiveness of several therapeutic approaches impacting our gut microbiota and improving our health. Among these, supplementation of the human diet with beneficial microorganisms (probiotics), substrates to promote the proliferation of these beneficial microbes (prebiotics), or a combination of both (synbiotics) represent the most investigated health interventions. 

    While often effective at eliciting helpful changes in aging biomarkers or deficits, supplementation with pre-, pro-, and synbiotics in clinical trials has revealed that there is no single intervention to benefit complex populations, mainly due to differences between individuals.  

    Takeaway 

    Aging is inevitable. But the frailty and diseases that often attend it may not be a sure thing.

    The gut microbiome offers a promising landscape to alter the course once thought certain in old age. Probiotics, prebiotics, and synbiotics may benefit through various mechanisms, including bolstering the immune system and reducing chronic inflammation. Specific strains of probiotics have shown potential but more research is needed.   

    Key references 

    Biagi, Elena et al. “Aging of the human metaorganism: the microbial counterpart.” Age (Dordrecht, Netherlands) vol. 34,1 (2012): 247-67. doi:10.1007/s11357-011-9217-5 

    Biagi, Elena et al. “Gut Microbiota and Extreme Longevity.” Current biology : CB vol. 26,11 (2016): 1480-5. doi:10.1016/j.cub.2016.04.016 

    Buford, Thomas W. (Dis)Trust your gut: the gut microbiome in age-related inflammation, health, and disease.” Microbiome vol. 5,1 80. 14 Jul. 2017, doi:10.1186/s40168-017-0296-0 

    Clegg, Andrew et al. “Frailty in elderly people.” Lancet (London, England) vol. 381,9868 (2013): 752-62. doi:10.1016/S0140-6736(12)62167-9 

    Collins, Stephen M et al. “The interplay between the intestinal microbiota and the brain.” Nature reviews. Microbiology vol. 10,11 (2012): 735-42. doi:10.1038/nrmicro2876 

    Coman, Vasile, and Dan Cristian Vodnar. Gut microbiota and old age: Modulating factors and interventions for healthy longevity.” Experimental gerontology vol. 141 (2020): 111095. doi:10.1016/j.exger.2020.111095 

    Fülöp, Tamas et al. “The Role of Immunosenescence in the Development of Age-Related Diseases.” Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion vol. 68,2 (2016): 84-91. 

    Grompone, Gianfranco et al. “Anti-inflammatory Lactobacillus rhamnosus CNCM I-3690 strain protects against oxidative stress and increases lifespan in Caenorhabditis elegans.” PloS one vol. 7,12 (2012): e52493. doi:10.1371/journal.pone.0052493 

    Jayanama, Kulapong, and Olga Theou. “Effects of Probiotics and Prebiotics on Frailty and Ageing: A Narrative Review.” Current clinical pharmacology vol. 15,3 (2020): 183-192. doi:10.2174/1574884714666191120124548 

    Kim, Sangkyu, and S Michal Jazwinski. “The Gut Microbiota and Healthy Aging: A Mini-Review.” Gerontology vol. 64,6 (2018): 513-520. doi:10.1159/000490615 

    Mackowiak, Philip A. “Recycling Metchnikoff: probiotics, the intestinal microbiome and the quest for long life.” Frontiers in public health vol. 1 52. 13 Nov. 2013, doi:10.3389/fpubh.2013.00052 

    Matsumoto, Mitsuharu et al. “Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production.” PloS one vol. 6,8 (2011): e23652. doi:10.1371/journal.pone.0023652 

    Nagpal, R et al. “Gut microbiota in health and disease: an overview focused on metabolic inflammation.” Beneficial microbes vol. 7,2 (2016): 181-94. doi:10.3920/bm2015.0062 

    Nagpal, Ravinder et al. “Gut microbiome and aging: Physiological and mechanistic insights.” Nutrition and healthy aging vol. 4,4 267-285. 15 Jun. 2018, doi:10.3233/NHA-170030 

    Nagpal, Ravinder et al. “Gut microbiome and aging: Physiological and mechanistic insights.” Nutrition and healthy aging vol. 4,4 267-285. 15 Jun. 2018, doi:10.3233/NHA-170030 

    Nakagawa, Hisako et al. “Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans.” Aging cell vol. 15,2 (2016): 227-36. doi:10.1111/acel.12431 

    Park, Mi Ri et al. Bacillus licheniformis Isolated from Traditional Korean Food Resources Enhances the Longevity of Caenorhabditis elegans through Serotonin Signaling.” Journal of agricultural and food chemistry vol. 63,47 (2015): 10227-33. doi:10.1021/acs.jafc.5b03730 

    Park, Mi Ri et al. Probiotic Lactobacillus fermentum strain JDFM216 stimulates the longevity and immune response of Caenorhabditis elegans through a nuclear hormone receptor.” Scientific reports vol. 8,1 7441. 10 May. 2018, doi:10.1038/s41598-018-25333-8 

    Ragonnaud, Emeline, and Arya Biragyn. “Gut microbiota as the key controllers of “healthy” aging of elderly people.” Immunity & ageing : I & A vol. 18,1 2. 5 Jan. 2021, doi:10.1186/s12979-020-00213-w 

    Ragonnaud, Emeline, and Arya Biragyn. “Gut microbiota as the key controllers of “healthy” aging of elderly people.” Immunity & ageing : I & A vol. 18,1 2. 5 Jan. 2021, doi:10.1186/s12979-020-00213-w 

    Salazar, Nuria et al. “Age-Associated Changes in Gut Microbiota and Dietary Components Related with the Immune System in Adulthood and Old Age: A Cross-Sectional Study.” Nutrients vol. 11,8 1765. 31 Jul. 2019, doi:10.3390/nu11081765 

    Sato, Yuko et al. “Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.” Nature vol. 599,7885 (2021): 458-464. doi:10.1038/s41586-021-03832-5 

    Sharma, Rohit, and Yogendra Padwad. “Probiotic bacteria as modulators of cellular senescence: emerging concepts and opportunities.” Gut microbes vol. 11,3 (2020): 335-349. doi:10.1080/19490976.2019.1697148 

    Tsai, Ying-Chieh et al. “Gerobiotics: probiotics targeting fundamental aging processes.” Bioscience of microbiota, food and health vol. 40,1 (2021): 1-11. doi:10.12938/bmfh.2020-026 

    Vaiserman, Alexander M et al. “Gut microbiota: A player in aging and a target for anti-aging intervention.”