Age-related diseases, therapies and gut microbiome: A new frontier for healthy aging

https://doi.org/10.1016/j.mad.2022.111711Get rights and content

Highlights

  • The gut microbiome is a lifelong companion vital to our health.

  • Microbiome imbalances are frequently observed in aging and age-related disorders.

  • Anti-age-related disease therapies interact bidirectionally with the gut microbiome.

  • Microbiome modulation is a new target of precision medicine for healthy aging.

Abstract

The gut microbiome is undoubtedly a key modulator of human health, which can promote or impair homeostasis throughout life. This is even more relevant in old age, when there is a gradual loss of function in multiple organ systems, related to growth, metabolism, and immunity. Several studies have described changes in the gut microbiome across age groups up to the extreme limits of lifespan, including maladaptations that occur in the context of age-related conditions, such as frailty, neurodegenerative diseases, and cardiometabolic diseases. The gut microbiome can also interact bi-directionally with anti-age-related disease therapies, being affected and in turn influencing their efficacy. In this framework, the development of integrated microbiome-based intervention strategies, aimed at favoring a eubiotic configuration and trajectory, could therefore represent an innovative approach for the promotion of healthy aging and the achievement of longevity.

Introduction

It is now a fact that the gut microbiota, i.e., the community of over 10 trillion microorganisms dwelling in our intestine, is a lifelong companion that actively and sometimes decisively contributes to our health (Turroni et al., 2018). Among the main drivers of its variation, there are a series of factors including minimally genetics and mostly variables related to the exposome, such as outdoor and occupational exposures, built environment, socio-economic factors, food and water contaminants, drugs and other aspects related to personal behavior, e.g., diet, lifestyle, physical activity, smoking, alcohol use, etc. (Deschasaux et al., 2018, He et al., 2018, Rothschild et al., 2018, Vujkovic-Cvijin et al., 2020). It is therefore not surprising that the gut microbiome predictably changes its compositional and functional profile from infancy to old age, following a sort of developmental trajectory along our life, parallel to major changes in the aforementioned variables (Kundu et al., 2017). Despite these changes, the microbiome continues to act as an ecosystem service provider, responding to precise physiological needs at different stages of life, at least until the microbiome-host relationship begins to crack due to progressive physiological changes in old age (Claesson et al., 2012). In this regard, the debate is still open on whether variations in the gut microbiome in elderly subjects are to be considered dysbiosis or adaptation to aged conditions, also considering the recent identification of potential longevity signatures in the microbiome profile (Biagi et al., 2017). On the other hand, it is known that imbalances in the gut microbiome can contribute to the onset and progression of disorders (and response to treatment), throughout our life, including those related to age, such as frailty, cardiovascular disease, and neurodegenerative diseases (such as Alzheimer and Parkinson) (Bosco and Noti, 2021, Buford, 2017). In this context, clinical intervention trials are accumulating that aim to explore the impact of microbiome modulation (or rejuvenation) on age-related decline in the musculoskeletal, cardiometabolic and nervous systems.

In this narrative review, we first summarize the state of the art on adaptive/maladaptive changes in the gut microbiome over age, up to the extreme limits of human life, and then discuss the potential involvement of the microbiome in age-related disorders, namely frailty and neurodegenerative diseases (i.e., Alzheimer and Parkinson), as well as hypertension and cardiovascular disease, as risk factors for the onset and acceleration of disability, and Down syndrome, as an example of accelerated aging. Particular attention will be paid to the bidirectional relationship between microbiome and anti-age-related disease therapies, and to the sometimes decisive effects on pharmacokinetics, side effects and drug response. Finally, we comment on the clinical trials that up to now have been designed to counter the age-related decline of the musculoskeletal system, mental and metabolic health, by restoring eubiotic profiles of the gut microbiome through prebiotics, probiotics, synbiotics and even fecal microbiota transplantation. While no results are yet available, the need to preserve our microbial counterpart for healthy aging and hopefully as the key to achieving longevity is increasingly evident. See Fig. 1 for a summary of the role of the gut microbiome in age-related disorders, including response to commonly prescribed medications, and the available microbiome manipulation tools that could help improve overall symptoms in the aging population.

Section snippets

Gut microbiome changes along aging

As mentioned above, the gut microbiome evolves with us throughout life. Of course, it is unclear whether its changes merely reflect secondary biological processes occurring at distinct life phases or whether it contributes to at least some age-related transitions, but its dynamics along aging are deemed increasingly worthy of further research for translations into clinical practice aimed at improving the health of elderly people. In this chapter, the main milestones of gut microbiome research

Gut microbiome dysbiosis in age-related diseases

Based on the above, it is not surprising that alterations in the gut microbiome have been shown to contribute to the onset and progression of numerous diseases throughout our lives, not just intestinal (Duvallet et al., 2017). Below we summarize the main changes observed in the composition and functionality of the microbiome in the context of age-related diseases, with particular regard to frailty, neurodegenerative diseases (such as Alzheimer and Parkinson), as well as hypertension and

Anti-age-related disease therapies and gut microbiome: a two-way relationship

The various chronic diseases that arise with increasing age (as discussed in the previous paragraphs) often involve taking multiple drug therapies, which can impact on the gut microbiome as well (Falony et al., 2016, Jackson et al., 2018, Maier et al., 2018), with potentially significant repercussions on the host health. On the other hand, there is a growing awareness of the role of the microbiome in influencing the fate and therefore the efficacy of drugs (Barone et al., 2021b, Klunemann et

Microbiome-based intervention strategies to combat aging and age-related diseases

Based on the above, it is not surprising that the gut microbiome is considered a strategic therapeutic target in the context of multiple disorders, including those related to age (Duvallet et al., 2017, Flanagan et al., 2020, Wilson and Nicholson, 2017). The development of microbiome-tailored intervention strategies aimed at restoring and maintaining a health-associated layout is indeed gaining increasing attention in the field of healthy aging, to address the specific needs of the elderly

Conclusions

The extension of lifespan on a global level does not always correspond to an equally positive healthspan. This trend has led to a growing need to identify new intervention strategies aimed at reducing the burden of age-related diseases, exerting overall geroprotective effects. In recent years, the fascinating role of the gut microbiome has emerged as a key contributor to host physiology and various pathological conditions, including those associated with the aging process. In this scenario,

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of interest

None.

References (215)

  • A. Cattaneo et al.

    Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly

    Neurobiol. Aging

    (2017)
  • M.G. Cersosimo et al.

    Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease

    Neurobiol. Dis.

    (2012)
  • Y.M. Chen et al.

    i TWK10 supplementation improves exercise performance and increases muscle mass in mice

    Nutrients

    (2016)
  • M. Derrien et al.

    Rethinking diet to aid human-microbe symbiosis

    Trends Microbiol

    (2017)
  • M. Derrien et al.

    The gut microbiota in the first decade of life

    Trends Microbiol

    (2019)
  • T.G. Dinan et al.

    Psychobiotics: A novel class of psychotropic

    Biol. Psychiatry

    (2013)
  • E. Flanagan et al.

    Nutrition and the ageing brain: Moving towards clinical applications

    Ageing Res Rev.

    (2020)
  • J. Halloran et al.

    Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice

    Neuroscience

    (2012)
  • L.J. Hickson et al.

    Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease

    EBioMedicine

    (2019)
  • L. Jochum et al.

    Label or concept - What is a pathobiont?

    Trends Microbiol

    (2020)
  • J.N. Justice et al.

    Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study

    EBioMedicine

    (2019)
  • J.L. Kirkland et al.

    Cellular senescence: a translational perspective

    EBioMedicine

    (2017)
  • T. Konikoff et al.

    Oscillospira: a central, enigmatic component of the human gut microbiota

    Trends Microbiol

    (2016)
  • S. Adnan et al.

    Alterations in the gut microbiota can elicit hypertension in rats

    Physiol. Genom.

    (2017)
  • E. Akbari et al.

    Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial

    Front Aging Neurosci.

    (2016)
  • V.N. Anisimov et al.

    Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice

    Cell Cycle

    (2011)
  • M.J. Armstrong et al.

    Diagnosis and treatment of Parkinson disease: a review

    JAMA

    (2020)
  • S.I. Arriola Apelo et al.

    Rapamycin: an inhibiTOR of aging emerges from the soil of Easter Island

    J. Gerontol. A Biol. Sci. Med Sci.

    (2016)
  • T.T. Ashburn et al.

    Drug repositioning: identifying and developing new uses for existing drugs

    Nat. Rev. Drug Disco

    (2004)
  • J.J. Augustine et al.

    Use of sirolimus in solid organ transplantation

    Drugs

    (2007)
  • C.J. Bailey

    Metformin: historical overview

    Diabetologia

    (2017)
  • D.J. Baker et al.

    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

    Nature

    (2011)
  • D.J. Baker et al.

    Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan

    Nature

    (2016)
  • M. Barichella et al.

    Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT

    Neurology

    (2016)
  • M. Barone et al.

    Over-feeding the gut microbiome: a scoping review on health implications and therapeutic perspectives

    World J. Gastroenterol.

    (2021)
  • M. Barone et al.

    Searching for new microbiome-targeted therapeutics through a drug repurposing approach

    J. Med Chem.

    (2021)
  • A.M. Baumann-Dudenhoeffer et al.

    Infant diet and maternal gestational weight gain predict early metabolic maturation of gut microbiomes

    Nat. Med

    (2018)
  • R.L. Bechshoft et al.

    Counteracting age-related loss of skeletal muscle mass: a clinical and ethnological trial on the role of protein supplementation and training load (CALM Intervention Study): Study protocol for a randomized controlled trial

    Trials

    (2016)
  • E. Bellikci-Koyu et al.

    Effects of regular kefir consumption on gut microbiota in patients with metabolic syndrome: a parallel-group, randomized, controlled study

    Nutrients

    (2019)
  • O. Benavente-Garcia et al.

    Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity

    J. Agric. Food Chem.

    (2008)
  • A. Benetos et al.

    Hypertension management in older and frail older patients

    Circ. Res

    (2019)
  • B. Bernardes de Jesus et al.

    The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence

    Aging Cell

    (2011)
  • E. Biagi et al.

    Gut microbiome in Down syndrome

    PLoS One

    (2014)
  • A. Bitto et al.

    Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

    Elife

    (2016)
  • I. Bjedov et al.

    The target of rapamycin signalling pathway in ageing and lifespan regulation

    Genes (Basel)

    (2020)
  • N. Bosco et al.

    The aging gut microbiome and its impact on host immunity

    Genes Immun.

    (2021)
  • S.L. Bowker et al.

    Glucose-lowering agents and cancer mortality rates in type 2 diabetes: Assessing effects of time-varying exposure

    Diabetologia

    (2010)
  • C.G. Buffie et al.

    Microbiota-mediated colonization resistance against intestinal pathogens

    Nat. Rev. Immunol.

    (2013)
  • C.G. Buffie et al.

    Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile

    Nature

    (2015)
  • T.W. Buford

    (Dis)Trust your gut: The gut microbiome in age-related inflammation, health, and disease

    Microbiome

    (2017)
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