How The Gut Microbiome Modulates Healthy Aging?

• Introduction
• The link between the gut microbiome and disease

  • Pathophysiology of disease and the gut microbiota
• How age influences the gut microbiome

  • The impact of residential care on the gut microbiota
• Identifying age-related shifts in gut microbiome composition

  • Observations from age-related differences
  • Microbial metabolites and host interaction
  • Urolithins
  • Further observations
• How can you define healthy and unhealthy aging?
• How to promote healthy aging

  • Probiotics and prebiotics
  • Could HMOs promote healthy aging?
  • Akkermansia
  • Dietary changes
• Summary 

Introduction

Aging is an inevitable evil for all of us; but why do some people age better than others?

This has been a hugely debated topic and one that we’re all desperate to know the answer to. Although there is no real definitive answer, it’s clear that genetic makeup, and environmental and lifestyle factors all contribute to healthy aging.

The role of the gut microbiome in aging is an important topic and could hold the key to longevity and health. In 2019, 703 million people across the world were aged 65 and over, this is predicted to rise to 1549 million people by 2050[i]. Although this is positive, it is evident that this will put increasing pressure on financial, health, and support services. So, understanding how we can promote healthy aging is paramount to not only undoing the burden on national services, but to also ensure we enjoy a happy, healthy, and fulfilled life.

Here, using a review by Ghosh et al., (2022), we explore the role of the gut microbial ecosystem in modulating healthy aging, how it can promote the development of chronic disease, and how it can be manipulated to help you age healthily.

The link between the gut microbiome and disease

Let’s start with the basics. The human gut microbiome is a unique and fascinating ecosystem that consists of bacteria, archaea, protozoa, and viruses[ii]. The myriad of microbes live in harmony, most of the time, colonising the gastrointestinal tract, co-existing with their human host.

Some of the key facts about the human gut microbiome include:

• It is populated by more than 100 trillion microorganisms[iii].
• It contains around 80% of the body’s immune cells.
• There are around 2000 bacterial species in the gut.
• The gut microbiome offers many benefits to the host for physiological, mental, and digestive health.

However, interest in the gut microbiota accelerated when research started to identify a link between disease and specific microbial metabolites.

Pathophysiology of disease and the gut microbiota

The table below highlights how changes in the gut microbiome can lead to the development of several chronic (and preventable diseases).

Table 1:The table demonstrates the potential role of the gut microbiome and the specific changes that are observed in chronic disease development.

Chronic disease	Role of gut microbiome in its development	Microbiome changes
Obesity	Dysbiosis in the gut can alter energy regulation, appetite, fat, storage, and inflammation[iv].	↑ Firmicutes to Bacteroidetes ratio   ↓ Microbial diversity
Type 2 diabetes	Dysbiosis increases insulin resistance and affects glucose metabolism.	↓ butyrate-producing bacteria, Bifidobacteria, Faecalibacterium, Akkermansia, Roseburia,and Bacteroides[v]
Inflammatory bowel disease (IBD)	Dysbiosis causes an imbalance between beneficial and opportunistic pathogens, increasing the risk of an abnormal immune response, and damage to the intestinal barrier[vi].	↓ Bifidobacterium, Bacteroides, Clostridium, Faecalibacterium prausnitzii, Roseburia, Suterella, Saccharomyces cerevisiae   ↑ Fusobacterium, Proteobacteria, Ruminococcus, Veillonellaceae[vii]
Cardiovascular disease	An imbalanced gut microbiome contributes to the development of narrow arteries (atherosclerosis) and high blood pressure (hypertension)[viii].	↑ Trimethylamine N-oxide production (TMAO)   ↑ Inflammation   ↑ Lipopolysaccharide production (LPS)
Allergies	Dysbiosis contributes to the development of allergies.	↓ Short-chain fatty acids (SCFAs)   ↓ microbial diversity[ix]
Colorectal cancer	Microbiome changes are associated with environmental and lifestyle factors, including diet and inflammation.	↑ proinflammatory opportunistic pathogens   ↓ butyrate-producing bacteria[x]
Neurodegenerative disease	The gut microbiome modulates the immune system and directs neural signaling, and immune responses via the gut-brain axis.	↑ Bacterial amyloids, LPS and other neurotoxic microbial molecules[xi]

 

How age influences the gut microbiome

For most of us when we think of aging we think about losing or graying of our hair, losing teeth, cognitive decline, and being less able to do many of the physical activities we could do when we were younger. But scientifically, aging is:

“the time-related deterioration of the physiological functions necessary for survival and fertility.”

Many of the cellular and molecular changes that occur with aging have been identified in humans, but these are accompanied by gut microbiome changes which can also affect the decline synonymous with age.

Source: Ghosh et al., (2022)

Figure 1.  Increasing age is linked to changes in the gut microbial balance that play a role in determining the rate of physical and mental decline. Lifestyle and environmental factors can have a detrimental effect on the delay of healthy aging or the acceleration of unhealthy aging. Ultimately, contributing to a decline in host health, quality of life, and a shortened lifespan.

That said, we don’t all age in the same way or experience the same illnesses, conditions, and symptoms, highlighting the variability of microbiome changes. There are a wealth of factors that can affect the gut microbiome as we age including:

• Deterioration of the digestive tract
• Lifestyle choices such as diet, reduced physical activity
• Environmental factors like medication and antibiotic use, surgery
• Social factors such as human and social contact, loneliness, whether you live alone, in your own home, or residential care

 

 Source: Ghosh et al., (2022)

Figure 2.  How individual age-related changes can impact the gut microbiome.

The impact of residential care on the gut microbiota

One of the interesting points raised in the review by Ghosh et al., (2022) was the effect of social factors on the composition of the gut. For example, research shows that people and families who live in the same household tend to share the same or similar microbiomes[xii]. Lax et al., (2014) demonstrated that a gut microbiota from a specific home could be matched to the specific family, while pathogenic strains on kitchen worktops could be identified on the host families' hands[xiii].

Further microbial changes can occur if the person resides in residential care, a common occurrence in the elderly population. Research by Haran and colleagues (2021) found that older adults living in a nursing home had a gut microbiome that reflected the medications they took, their age, frailty, and living location. The researchers also identified that the gut microbiome changes over time following admission to the care home, demonstrating a time-dependent shift towards dysbiosis[xiv].

Identifying age-related shifts in gut microbiome composition

To identify the changes in the gut microbiome of older people, studies have focused on two specific categories:

1. Age-related differences
2. Gut microbiome changes linked to specific age-related disorders

Figure 3.  Nagpal et al., (2017) highlighted the change in microbiota composition across the human lifecycle. The most prominent changes occur during infancy and old age, which is coincidentally when our immune system is most volatile[xv].

Observations from age-related differences

Interestingly, despite old age being a vulnerable time for our gut microbiome, many studies have delved into the centenarian microbiome. Generally, research has shown that centenarians have a:

• reduced abundance of friendly species like  Faecalibacterium  linked to good health in younger people
• increased abundance of other health-promoting species, such as  Akkermansia  and disease-promoting microbes

Overall, different studies have found similar results when analysing extreme aging-linked microbiome signatures, despite variation in the demographics of population studies. Researchers have also found that the bacterial diversity in the gut can overlap with age-related microbiome changes which can be characterised by:

↓ Prevotella ↓Faecalibacterium ↓ Eubacterium rectale ↓ Lachnospira ↓ Coprococcus ↓ Bifidobacteria	Commensal bacteria:
	↑ Akkermansia ↑ Christensenllaceae ↑ Butyricimonas ↑ Odoribacter ↑ Butyricicoccus
	Pathobionts (bacteria that can cause harm in certain conditions):
	↑ Eggerthella ↑ Bilophila ↑ Fusobacteria ↑ Streptococcus ↑ Enterobacteriaceae

 

The changes in the microbiota composition define those linked to aging and age-related health decline, as shown in Figure 4.

Figure 4.  Ghosh et al., (2022) found that consistent changes in microbial taxa were identified across the two types of studies (gut microbiome vs. aging and gut microbiome differences between healthy and unhealthy individuals). They found three major bacterial taxa groups and analysed how they changed with age. Group 1 reduced with age and was linked to healthy aging (increased physical activity, good diet, low cognitive decline, and longevity). Group 2 had a higher abundance of pathobionts that increased with age, and were linked to unhealthy aging, including factors such as frailty, obesity, low exercise rates, medication use, and chronic disease. Group 3 increased with age and in healthy aging.   

Dejong et al., (2020) conducted a meta-analysis consisting of more than 2500 metagenomic datasets from people aged 20 to 89. They identified 6 microbial taxa groups characterised by their association with disease-associated abundance changes across different age groups. These disease-linked groups can be summarised as follows:

• G1: Elevated across all ages in multiple diseases.
• G2: Elevated in older individuals (≥60 years) in multiple diseases.
• G3: Elevated in younger/middle-aged (20-60 years) in multiple diseases.
• L1: Depleted across all ages in multiple diseases.
• L2: Depleted in older individuals (≥60 years) in multiple diseases.
• L3: Depleted in younger/middle-aged (20-60 years) in multiple diseases.

Importantly, the members of G1 found to be increased in many diseases across all ages were also linked to an increase in frailty in another study, called the ELDERMET project, which are consistent with the pathobionts in group 3 displayed in Figure 4. The bacterial taxa in these groups were associated with an increase in the production of ethanol, trimethylamine, and other harmful metabolites, linked to inflammation, aging, and the development of chronic disease.

Microbial metabolites and host interaction

These metabolites are not the only ones identified that can have an impact on host metabolism, inflammation and disease risk. Some other identified metabolites and the diseases they are associated with were:

Group 2

• Para-cresol
  • Cognitive disorders
  • Chronic kidney disease
• Lipopolysaccharide
  • Metabolic syndrome
  • Inflammation

But Groups 1 and 3 show increases in metabolites which have positive benefits for human health, particularly:

• Butyrate
• Acetate

Butyrate is an important short-chain fatty acid produced by commensal gut bacteria. It has some potent properties, including:

• It’s the main energy source for cells that line the colon.[xvi]
• Increasing antioxidant levels to reduce inflammation and strengthen the gut barrier.
• It’s a histone deacetylase (an enzyme produced in many cancers) inhibitor, so it can cause cell death (apoptosis), preventing cancer cells from developing.[xvii]
• It protects against metabolic disease e.g., obesity and type 2 diabetes.
• It may protect against neurodegenerative diseases, like Alzheimer’s and Parkinson’s.[xviii]

These properties may also have an important role in preventing unhealthy aging because although healthy older people appear to lose Group 1 microbes, this loss is compensated by the gain of alternative butyrate producers in Group 3, like:

• Odoribacter
• Butyricimonas
• Butyrivibrio
• Oscillospira

As well as an increased abundance of butyrate producers, an increase in  Akkermansia  could also have beneficial effects for aging. A study by Ma et al., (2023) investigated the effects of gut microbiome remodeling on age-related disorders through  A. muciniphila.

In unhealthy aging,  Akkermansia muciniphila  abundance is low. By remodeling the gut microbiota of old mice by fecal microbiota transplantation (FMT) from young mice, the researchers demonstrated increased  A. muciniphila  abundance and improved age-related disorders.

Figure 5.  In control mice where unhealthy aging had occurred, glucose sensitivity was reduced, enlargement of the liver and spleen (hepatosplenomegaly) was present, low abundance of A. muciniphila, and loss of tight junctions and inflammaging were all observed. However, following FMT, all of these were reversed, suggesting that interventions that increase  Akkermansia muciniphila  could be an effective way to promote healthy aging.

Urolithins

Urolithins are an emerging and interesting class of gut microbiome-derived compounds, produced from plant components, such as ellagic acid.

Previous research has shown that individuals can be divided into three urolithin metabotypes:

1. UM-A  yields urolithin A
2. UM-B  yields urolithin-A and isourolithin-A
3. UM-O  yields no urolithins

Urolithin A has many purported health benefits, including for age-related conditions.

Source: D’Amico et al., (2021)

Figure 6.  Urolithin A is converted from ellagitannin and ellagic acid-rich foods, like pomegranate and walnuts by specific gut microbiome members. Urolithin A then goes on to influence several health areas[xix].

The metabotype associated with urolithin A production, UM-A, is only present in around 40% of people and is thought to decline with age. However, for age specifically, urolithin A is a promising strategy for targeting mitochondrial and muscle dysfunction, common with increasing age.

A UM-B metabotype, which yields urolithin-B and isourolithin-A as well as urolithin-A, is found in a higher percentage of overweight or obese individuals (31%), suggesting weight gain favours urolithin B and isourolithin-A producers[xx].  Interestingly, UM-B increases the levels of isourolithin A which is associated with an unknown member of the  Eggerthellaceae  family – a member of the Group 3 microbial taxa, suggesting an affiliation with unhealthy aging.

Further observations

Differences in age-linked microbiome changes can vary across studies. For example:

• Roseburia  abundance is significantly reduced in Italian, Irish and Thai people, but increased in Russian, Chinese, and Korean populations.
• The pathobiont  Bacteroides fragilis  decreased with age in a healthy Indonesian cohort, contrary to other age-associated studies.

These differences may reflect ethnic, dietary, geographical, and lifestyle variations.

Sex and age differences:

• Younger people have more pronounced sex-dependent microbiome composition (beta diversity) differences
• Women have a higher alpha diversity than men

How can you define healthy and unhealthy aging?

Characterising these two cohorts isn’t easy, especially across a wide range of age groups, because it can occur at any age, even in centenarians. However, there appear to be differences in the composition of the gut microbiome that may reflect healthy and unhealthy phenotypes.

Despite variations across studies, consistent patterns in microbial alterations suggest their biological significance, providing a foundation for developing microbiome-based interventions to combat unhealthy ageing.

How to promote healthy aging

Resetting the gut microbiome, specifically targeting the signals of unhealthy aging is an emerging area of research. Microbiome-based interventions include:

• Prebiotic supplements
• Synbiotics
• Postbiotics
• Fecal microbiota transplantation
• Health-promoting diets

These therapeutic regimens are designed to reverse or halt the aging process that promotes physical and mental decline. This is often enhanced by a microbiome that favours disease, such as the changes seen in Figure 4. Here, the increases in Group 2 microbiota and the depletion of health-promoting Group 1 and 3 members drives unhealthy aging.

The problem is, there are very few studies that investigate microbiome interventions that promote healthy aging in older people. The review by Ghosh et al., (2022) identified just five with a sample size of more than 100, and there are still limitations, including:

• Use of low-resolution microbiome profiling
• Focus on the effect of the intervention on physiology rather than aging
• Most studies do not perform any microbiome profiling and rely on physical and wellbeing changes to draw conclusions
• Effectiveness rates vary
• FMT is often used in older people to treat difficileinfections

However, the limitations in current studies, do mean we should be hopeful of the effects targeted microbiome interventions could have on unhealthy aging.

Let’s look at why.

There’s still hope for microbiome target interventions

The effectiveness of microbiome-targeted interventions, such as probiotics and prebiotics, varies by type, duration, and dosage. Dietary supplements used in this way aim to increase beneficial bacteria (Lactobacilli,  Bifidobacteria,  butyrate producers,  Akkermansia), the ones that are often reduced in unhealthy aging microbiomes, enhance insulin sensitivity, intestinal barrier integrity, and overall health. Studies report benefits like reduced insulin resistance, inflammation, and improved cognitive and cardio-metabolic health, all markers of aging. This is summarized in Figure 7.

Figure 7.  How specific targeted interventions can change the composition of the gut microbiome to prevent age-related decline.

Probiotics and prebiotics

The administration of probiotics and/or prebiotics often focuses on their ability to boost the abundance of beneficial microbes and enhance their activity. Studies have shown that probiotics can regulate imbalances in the gut associated with age by promoting healthy strains[xxi].

Bifidobacteria  and  Lactobacilli  are known for their effect on strengthening the gut barrier, increasing insulin sensitivity and cross-feeding other useful bacteria, including butyrate producers.

Some of the benefits of probiotics in the elderly are:

• Prevention of diarrhoea-associated disease
• Improved intestinal barrier function
• Defense against pathogens
• Improved gut motility and intestinal inflammation
• Enhanced immunity
• Prevention of colon cancer[xxii]

Did you know?Human milk oligosaccharides (HMOs) are a type of prebiotic known to boost the abundance and activity of  Bifidobacteria  and  Akkermansia.Why not explore our range?

Could HMOs benefit the aging process?

Lots of research has shown that HMOs have benefits for both infants and adults. HMOs are fundamental in laying the foundations for the developing infant gut, leading to research into their effect across all age groups. Some of the benefits of HMOs in adults include:

• Promotion of beneficial bacteria
• Preventing the colonization of pathogens
• Enhancing immunity
• Supporting cognitive functions
• Anti-inflammatory benefits
• Allergy prevention
• Strengthened intestinal barrier
• Improved metabolic health[xxiii]

All these factors could benefit the aging process and maintain the health-promoting taxa linked to the healthy aging process.

In addition, Wang et al., (2022) demonstrated that supplementation of 2’-Fucosyllactose (2’-FL) in aging mice reduced oxidative stress and intestinal inflammation. It also improved the gut barrier function, increased the production of short-chain fatty acids, and enhanced the abundance of probiotic bacteria, including  Akkermansia.Finally, the researchers noted that 2’-FL prevented cell death in the brains of aging mice[xxiv] and increased the expression of sirtuin1 (SIRT1), a protein known to reduce age-related disease and prolong a healthy lifespan.

Figure 8.You can support your gut microbiome and promote healthy aging with our PureHMO® Prebiotic Powder, delivering nothing but 1950 mg of 2’-FL in one scoop.

Akkermansia

Akkermansia  abundance is a sign of healthy aging. A study involving 32 people aged 18-70 found that giving a live or pasteurized  Akkermansia  supplement to overweight or obese insulin-resistant volunteers for 3 months was safe and effective. The results showed that  Akkermansia:

• improved insulin sensitivity and total cholesterol
• lowered body weight and hip circumference
• reduced circulating biomarkers for liver dysfunction and inflammation[xxv]

Similarly, mice studies have shown that  Akkermansia  supplementation strengthens the gut lining, maintains gut homeostasis, restores cognitive function, and prolongs life in aged mice[xxvi]. 

Bárcena et al., (2019) demonstrated that correcting the imbalance in gut microbes associated with accelerating aging is beneficial. They found that FMT from wild-type mice increased lifespan and improved health, while transplantation of  Akkermansia  had even greater benefits[xxvii].

Figure 9.  Get ahead of the trend and order a pot (or two) of our Akkermansia  muciniphilaDaily Probiotic.

Dietary changes

On top of probiotic and prebiotic supplementation, whole dietary changes can have promising effects on resetting the gut microbiome. The NU-AGE project investigated the effects of a year-long intervention of the Mediterranean Diet (MedDiet) on the gut microbiota and aging.

The MedDiet is classified by:

Increased intake of:

• Vegetables
• Fruits
• Legumes
• Olive oil
• Fish
• Nuts

Reduced intake of:

• Red meat
• Saturated fat
• Dairy

The overall results of the study found that the MedDiet changed the composition of the gut microbiota and improved frailty, cognitive function and reduced inflammatory biomarkers, such as interleukin-17 and C-reactive protein[xxviii]. Strict adherence to the diet retained key health-promoting species such as  Faecalibacterium prausnitzii,  a key butyrate producer and Roseburia, and reduced significant pathobionts. Therefore, the study demonstrated the power of the MedDiet to ‘reset’ the gut microbiome for the promotion of healthy aging.

Further research shows that the MedDiet has positive effects on biological aging. An increased intake of polyphenols, particularly green types could slow the biological aging process[xxix].

Summary

Our understanding of the gut microbiome and its impact on health and disease is expanding, and science is just embarking on the journey to understanding the link between the gut and aging.

Although there is still so many questions to answer, what is clear is that the gut microbiome does have some influence over how ‘well’ or ‘healthily’ humans age. Microbiome composition changes have been identified in the development of disease, a marker of aging, as well as increasing age, further demonstrating that the human microbiome is not a static entity.

Targeted microbiome interventions, such as dietary changes, probiotics, prebiotics, and even FMT, which aim to ‘reset’ the microbial composition, could become personalised to manipulate the gut to provide us with a more positive aging process.

Written by: Leanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome.  

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