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ScienceDirect
Understanding the impact of age-related changes in the
gut microbiome on chronic diseases and the prospect of
elderly-specific dietary interventions
Paola Pellanda1,2,3, Tarini Shankar Ghosh1,2,3 and
Paul W O’Toole1,2
Ageing is associated with characteristic changes including a
gradual decline of physiological functions, inflamm-aging,
sarcopenia, and the associated onset of multiple diseases.
Another factor potentially contributing to enhanced
susceptibility to multiple diseases is aging-associated
alteration in the gut microbiome. These alterations include a
loss of commensals and gain of disease-associated
pathobionts, and are accelerated by lifestyle factors like
medication, reduced mobility and restricted diet.
Several studies suggest that supplementation or modification
of the habitual diet may help to address age-related frailty and
comorbidities, aided by microbiota modulation. In this review,
we comprehensively summarize recent investigations of
microbiota alterations during aging and age-related diseases
and the possibilities for altering the microbiome as a
therapeutic approach.
Addresses
1
APC Microbiome Institute, Bioscience Building, University College
Cork, Ireland
2
School of Microbiology, Food Science & Technology Building,
University College Cork, Ireland
Corresponding author: O’Toole, Paul W (pwotoole@ucc.ie)
3
Contributed equally.
Current Opinion in Biotechnology 2021, 70:48–55
This review comes from a themed issue on Food biotechnology
Edited by Anna E Thalacker-Mercer and Martha Field
https://doi.org/10.1016/j.copbio.2020.11.001
0958-1669/ã 2020 Elsevier Ltd. All rights reserved.
Introduction
Aging is associated with the decline of multiple physiologi-
cal functions (including the onset of a chronic inflammation
state called inflamm-aging), metabolic dysregulation,
increased prevalence of non-communicable diseases/dis-
orders (extensively reviewed in Refs. [1,2]). These factors,
along with the ensuing changes in life-style habits, like
reduced quality of diet and physical activity and increase in
Current Opinion in Biotechnology 2021, 70:48–55
medication intake, substantially affect the gut microbiome
composition [3]. Recent studies from our group as well as
others have indicated that these microbiome changes can
be further correlated with the risk or onset of several age-
related pathologies [4–7,8,9].
Adopting optimal dietary regimes like the Mediterranean
Diet (MedDiet) has been shown to have a multitude of
beneficial effects on host health, including reduced inci-
dence of chronic diseases, inflammation, cognitive
decline and physical frailty [10]. Besides playing a key
role in host physiology, the gut microbiome of an indi-
vidual is also amenable to modulations through external
factors like diet. In this context, a recent large-scale
MedDiet intervention study from our group indicated
that many of the beneficial effects of the MedDiet could
be mediated by an internal gut microbiome response that
can potentially reverse the effects of the bidirectional
interactions between age-related physiological decline
and gut microbiome alterations [11]. Reducing aging-
associated physiological decline through diet-based mod-
ulation of the microbiome can thus be a key therapeutic
strategy [11,12].
In this article, we first present an overview of how age-
related changes in the human microbiome can further
increase the susceptibility of the host to age-related
diseases and metabolic disorders. We subsequently focus
on the results of recent studies that show how adoption of
optimal dietary habits like the MedDiet can help reverse
these effects and reduce age-associated physiological
decline and frailty.
Bidirectional interaction between the aging
phenotype and gut microbiome resulting in
progressive decline of health status
Aging is a progressive biological process, characterized by
specific hallmarks (reviewed in detail in [1] and schemat-
ically summarized in Figure 1). A culmination of these
processes results in the onset of frailty, cognitive decline,
increased incidence of chronic diseases and subsequent
changes in lifestyle like reduced quality of diet, lower
physical activity, increased medication and surgeries.
Each of these factors have a considerable effect on the
gut microbiome composition. A subset of these modula-
tions can make the host even more susceptible to age-
related chronic diseases and disorders, resulting in a
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 Age-related changes in the gut microbiome Pellanda, Ghosh and O’Toole 49

Figure 1

Current Opinion in Biotechnology

The hallmarks of aging.

Bi-directional interaction between aging-associated physiological changes, onset of chronic diseases, and subsequent changes in life-style habits
and the gut microbiome (indicated as black bold arrows). Various aging-associated changes in the host drive shifts in the gut microbiome. These
shifts in the gut microbiome can in turn detrimentally impact various aspects of host health (indicated as split red-arrows).

bidirectional vicious cycle of increasingly declining
health status. Some of these examples are described
subsequently and schematically summarized in Figure 2.
One of the key consequences of aging is immune dys-
regulation. This age-related dysregulation of the
immune system, as well as the associated adverse clinical
change, is known as ‘immuno-senescence’ [13]. Among
the aging-associated changes in the immune system, of
note are the decline in the naı̈ve T and B cells repertoire,
the accumulation of memory/effector cells [14,15], and
the increased levels of pro-inflammatory markers [14].
Thus, immuno-senescence is not only responsible for
reduced host response to opportunistic infections, but
also promotes a chronic and systematic low-grade state of
inflammation known as ‘inflamm-aging’ [16]. The
increased levels of pro-inflammatory interleukins (IL-6
and IL-8) in older adults appear to be associated with a
relative decrease of the health-promoting short-chain
fatty acids (SCFAs) producing Lachnospiraceae, and an
increase of colitis-promoting Erysipelotrichaceae, suggest-
ing an altered immune response leads to microbiome
alterations that are even more detrimental for the host
[3,13,17] (Figure 2). A decrease in mucin production
results in alterations in the proportional composition of
the mucin-metabolizing taxa in the SCFAs-producing
Clostridiaceae, Bacteroidaceae and the probiotic neuro-
transmitter producing Bifidobacteriaceae families [3,18],
thereby driving the host towards cognitive decline.
Increased inflammation status, associated with loss of gut
barrier and opportunistic pathogen infections, along with
other factors like reduced SCFAs, Folic acid, Vitamin B12
and Flavonoid production, can also contribute further to
reduction of skeletal and muscular health, resulting in
sarcopenia (Figure 2b) (reviewed in Refs. [8,19]). On
similar lines, post-menopausal women, for example, are
frequently affected by osteoporosis, which has been asso-
ciated with microbiome alterations [20,21]. The micro-
biome of patients with osteoporosis is characterized by
higher abundance of Actinomyces and Eggerthella genera
compared to healthy controls [21]. The associations
reported for the gut microbiome are not limited to bone
homeostasis but include indices for the maintenance of
muscle function and the onset of sarcopenia.
Another age-related phenotype is cognitive decline.
Emerging evidence has indicated the importance of
the gut microbiota-brain communication axis in human
mental health [8,22]. Some of the key mechanisms by
which age-associated gut microbiome functional dysbio-
sis could contribute to cognitive decline include reduced
biosynthesis of neuro-transmitters, like serotonin and
gamma-aminobutyric acid, increased production of

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50 Food biotechnology

Figure 2

(a)

(b)

Current Opinion in Biotechnology

Microbiome changes associated with age-related diseases.

(a) Examples showing how aging associated phenotypic changes in life-style and physiology can cause dysbiotic modulation of the gut
microbiome and how these modulations are positively linked with the onset of multiple chronic diseases and disorders. (b) Schematic flow-based
representation showing how functional changes resulting from the aging-associated changes in gut microbiome can result in cognitive decline and
physical frailty.

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 Age-related changes in the gut microbiome Pellanda, Ghosh and O’Toole 51
amyloid proteins and amyloidogenic bacterial compounds
as well as the detrimental metabolite p-Cresol, and
reduced SCFAs production [8,23,24]. Alzheimer’s dis-
ease (AD) is the most common form of dementia among
elderly subjects. In recent years, the inflammatory-infec-
tious hypothesis has been proposed regarding AD patho-
genesis: inflamm-aging and the alteration of the gut
microbiome could dysregulate the gut-brain axis thereby
triggering or exacerbating the AD pathology [25,26]. In
addition to changes in the microbiota composition, the
progression of cognitive impairment is reportedly associ-
ated with an increase in the serum levels of secondary bile
acids, bacterial metabolites which are able to cross the
blood-brain barrier [9,27].
One of the most common clinical syndromes associated
with aging is frailty, a complex condition characterized
by multi-organ dysregulation. Frailty is often associated
with malnutrition, reduced mobility and residence in
nursing homes. A recent study from our group observed
that the microbiome alterations associated with certain
diseases vary with the subjects’ age [28]. This meta-
analysis investigated more than 2500 gut microbiomes
published datasets, including individuals aged 20–89
with Inflammatory Bowel Disease (IBD), liver cirrhosis,
type-2 diabetes (T2D), intestinal polyps, or colorectal
cancer (CRC). Notably, we also identified a specific set
of taxa that were not only increased in multiple diseases,
but also significantly associated with increasing frailty in
the ELDERMET cohort. It was difficult to ascertain if
these modulations of the gut microbiome were a cause
or consequence. Using information from previously
metabolic capabilities and gene presence/absence, we
saw an enrichment of capabilities linked to the produc-
tion of specific metabolites that have been previously
shown to be associated with the onset of multiple
diseases (schematically indicated in Figure 2). These
included metabolites like Trimethylamine (TMA), sec-
ondary bile acids and p-Cresol. We also observed a
reduction of taxa known to produce SCFAs, metabolites
that have been negatively linked to multiple diseases
and metabolic disorders/abnormalities like chronic
inflammation, insulin resistance, cognitive decline, obe-
sity, epigenetic dysregulation, and impaired barrier
function. In other words, age-related onset of frailty is
associated with specific bacterial members that have
been functionally linked with metabolic capabilities
that can make the host increasingly susceptible to mul-
tiple clinical disorders (indicating a causative role of the
gut microbiome).
A direct consequence of aging-associated detrimental
changes in health status is an increase in medication intake.
Different studies have investigated the effects of the most
commonly used drugs on the composition and metabolic
function of the gut microbiota. Intake of opioids, paraceta-
mol or proton pump inhibitors are associated with elevated
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abundance of taxa belonging to families Streptococcaceae,
Gemellaceae, Peptostreptococcaceae and Fusobacteriaceae and a
decrease in the abundance of SCFAs-producing taxa like
Roseburia and Eubacterium rectale [29,30]. Notably, taxa,
belonging to the families of Fusobacteriaceae (Fusobacterium
nucleatum), Peptostreptococci (Peptostreptococcus stomatis) and
Gemmellaceae (Gemmella morbillorum) have been shown,
reproducibly across multiple cohorts, to be enriched in
the gut microbiome of CRC patients [31,32], along with
two microbial pathways, namely choline metabolism to
trimethylamine and secondary bile acids production (a
metabolic signature that is also associated with frailty
onset). The meta-analysis by Ghosh et al. further identified
a significantly increased prevalence of these taxa in older
adults, further confirming the age-associated increase of
these pathobionts [28]. Another taxonomic group that has
been associated with multiple medication intake is
Streptococcaceae. Besides being associated with opportunis-
tic pathogenic infections, taxa belonging to this group were
also observed to show significantly positive associations
with the onset of multiple diseases [28]. Thus, increase in
medication intake, that is expected to ameliorate the
effects of diseases and physiological dysfunction, can also
drive gut microbiome changes that are functionally even
more detrimental to the host, thus acting as an element of
this vicious cycle.
Another consequence of aging-related pathophysiologies
is the gradual decline of dietary quality. The amount of
microbiota-accessible carbohydrates (MACs), especially
fibre, consumed daily often decreases during aging, most
likely as a result of physiological changes such as reduced
sense of taste, loss of appetite, and poor dentation.
Reduced dietary quality can also result from complica-
tions like diseases, surgical procedures as well as due to
intake of specific medications. This decrease in MACs
intake is associated with the loss of fibres-responsive
species such as Faecalibacterium and Roseburia [33,34],
which eventually produce SCFAs, the key metabolites
to maintaining gut homeostasis and host health.
Thus, to summarize, aging-associated physiological and
life-style changes described above negatively impact the
crosstalk between the host and commensal gut microbes,
and are associated with microbiome shifts to a disease-
like state. Alarmingly, these changes in the composition
of the gut microbial community create a metabolic milieu,
that in turn can have further damaging effects on the well-
being of an individual. However, unlike the host genome
function, the gut microbiome can be subjected to thera-
peutic modulations like adoption of beneficial dietary
intervention regimes (Figure 3a). Investigating these
microbiome alterations could thus be helpful for the
development of diet-based therapeutic strategies for
older people. In contrast to medications, adoption of
optimal dietary habits is cost-effective, can be applied
at a population level and is relatively free of side-effects.
Current Opinion in Biotechnology 2021, 70:48–55
52 Food biotechnology

Figure 3

(a)

(b)

Current Opinion in Biotechnology

Potential benefits of dietary interventions on microbiome and health.

(a) Diet based modulation of the gut microbiome holds a promise as a key therapeutic strategy to break the vicious cycle of the aging-associated
phenotype impacting the gut microbiome in a manner that leads to further deterioration. Unlike the host genome, the gut microbiome is amenable
to modifications using Optimal dietary regimes. One of which is the Mediterranean Diet. (b) Examples showing how specific dietary regimes or
administration of prebiotics can modulate the microbiome in a manner that metabolically breaks the vicious cycle described in Figures 2 and 3a.

We will discuss one such dietary intervention regime, studies specifically focussed on the elderly are currently
namely the MedDiet in the subsequent section. limited.

Dietary interventions in elderly: the A recent six-months prebiotic intervention performed by

Mediterranean Diet as a strategy to combat
frailty
Diet is a key modulator of the microbiome, as the intake
of specific dietary components can either feed or inhibit
the growth of specific members of gut microbial commu-
nity. A large multitude of studies exploring these aspects
have highlighted fairly consistent patterns [35], schemat-
ically shown in Figure 3b. For example, intake of pre-
biotics, like galacto/fructo/arabino-xylo-oligosaccharides,
Polydextrin and resistant starch have been associated
with relative increase of probiotic bacteria (Bifidobacter-
ium and Lactobacillus). A diet enriched in MACs like fibres
leads to the enrichment of fibrolytic organisms, capable of
producing SCFAs, like butyrate and propionate [36].
Therefore, modulating the gut microbiota by diet could
be a productive approach to prevent or treat frailty and
other aging-associated detrimental changes in the elderly.
Despite the promise, extensive dietary intervention
our group investigated the effect of a mixture of five
prebiotics on the gut microbiota of elderly [37]. The
effect of diet supplementation with a mix of wheat
dextrin, resistant starch, polydextrose, soluble corn fibre,
and galactooligo-saccharide were compared with a pla-
cebo treatment with maltodextrin, known to have a
modest effect on the microbiome. Although we failed
to detect a significant overall change in the microbiota
diversity in any of the intervention groups, specific
health-associated taxa such as Ruminococcaceae and Phas-
colarctobacterium, responded positively to the intervention
[37]. These results suggest that global modifications in
human microbiota may require more dramatic dietary
changes.
A promising dietary model is the so-called Mediterranean
diet. The MedDiet consists of a higher intake of plant-
based foods, as vegetables and fruits, nuts, whole grain

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 Age-related changes in the gut microbiome Pellanda, Ghosh and O’Toole 53
and legumes, olive oil as main source of fat; reduced
consumption of unsaturated fat, alcohol, red meat and
processed cereals. Increased adherence to the MedDiet
regime has been associated with specific beneficially
outcomes in the elderly. Other studies have identified
higher adherence to MedDiet to be associated with
reduced cognitive decline and improved brain volume
in the elderly and most importantly with reduced frailty
(reviewed in Ref. [38]).
While the mechanistic basis of the beneficial effects of
the MedDiet is still not clear, one of the ways by which
the MedDiet could exert its impact is through modulation
of the gut microbiome (Figure 3b). One of the first studies
to focus on the composition of the gut microbiome of
people consuming MedDiet revealed that higher adher-
ence to the MedDiet positively correlated with higher
abundance of Prevotella and fibre-degrading Firmicutes
[39]. The potential of the MedDiet to reverse the micro-
biome alterations associated with a pathophysiology was
recently revealed by a small intervention study in
20 elderly obese women [40], where in MedDiet adher-
ence significantly counteracted the lower abundance of
Akkermansia and Parabacteroides as well as of SCFAs
producers observed in obese subjects and lowered the
abundance of Collinsella, typically associated with obesity.
The possibility of exploiting the MedDiet to improve
older adults’ health was comprehensively investigated by
the European Commission-funded project NU-AGE
(‘New Dietary strategies addressing the specific needs
of the elderly population for healthy aging in Europe’).
More than 1000 community-dwelling elderly people,
aged 65–79, were recruited in five different countries
(Italy, France, Poland, Netherlands, and the UK) for a
1-year randomized, single-blind, controlled trial, with two
parallel arms: control versus MedDiet group [12]. The
NU-AGE MedDiet intervention showed a positive
impact on age-related syndromes, including significant
improvement in global cognition, episodic memory, blood
pressure and arterial stiffness, improved innate immune
response and reduced rate of bone loss in individuals with
osteoporosis [41–44].
The microbiome response to NU-AGE MedDiet con-
sumption in more than 600 subjects was systematically
analysed by our group [11]. Using Random Forest
models, we identified Operational taxonomy units
(OTUs) that responded positively or negatively to the
MedDiet intervention (referred to as diet-positive or diet-
negative, respectively). Interestingly, the pattern of asso-
ciations of these taxa remained consistent across nation-
alities despite significant variations in the baseline diet.
The diet-negative OTUs belonged to species previous
known to be associated with diseases like CRC, athero-
sclerosis, cirrhosis. One of the crucial impacts of the
MedDiet intervention was evident when we
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computationally predicted the metabolic changes puta-
tively associated with these gut microbiome modulations.
The MedDiet associated gut microbiome modulations
was predicted to be associated with significantly lower
levels of p-Cresol, hydrophobic secondary bile acids and
TMA, the same set of detrimental metabolites associated
with the onset of frailty and multiple chronic diseases
(Figures 2 and 3). Many of these metabolic predictions are
also observed experimentally in studies investigating the
faecal metabolome of individuals on MedDiet or fibre-
based diets [45,46]. This indicates that the MedDiet can
potentially reverse the detrimental effects of aging-asso-
ciated phenotype on the gut microbiome, thereby break-
ing the vicious cycle of decline in health status.
Instead, diet-positive OTUs were mainly assigned to
species previously associated with SCFAs production,
and depleted in chronic diseases (like Roseburia, Eubacte-
rium, Faecalibacterium, and Anaerostipes hadrus). Notably,
these Diet-positive OTUs were not only associated with
improved cognitive function measures and reduced
inflammation and frailty, but were also observed to be
acting as key-stone species in the gut microbial commu-
nity. In contrast, they were negatively associated with
frailty and pro-inflammatory markers. These results sug-
gest that a fibre-rich diet, such as the MedDiet, can be a
powerful tool to modulate the gut microbiota, maintain
gut homeostasis and consequentially improve human
health.
Conclusions
Scientific and medical advances have significantly
increased human life span. Now the challenge has shifted
to maintaining a healthy aging population. Older adults
are more susceptible to chronic diseases; therefore, many
efforts are aimed at improving the understanding of the
onset and development of such pathologies. One of the
most promising research avenues is microbiome-aging
interaction. Modulation of the gut microbiota has shown
encouraging results in some disorders, such as T2D,
obesity, and osteoporosis. Successful modulation of the
gut microbiome is still challenging, as many aspects of
microbiome-host interaction are still unknown.
Mild interventions, such as supplementation with pre-
biotics and probiotics, despite inducing changes in the gut
microbiota composition, may be not strong enough to
affect human health in the long term. The NU-AGE
MedDiet consortium has shown that increased compli-
ance to a complete reprogramming of the habitual diet
can potentially alter the deep-seated microbiome struc-
ture of the human gut in manner that positively improves
many age-related conditions, reducing frailty. However,
many of the associations observed in the NU-AGE Med-
Diet study were relatively weak, indicating longer dura-
tions of the intervention and/or personalized (or stratified)
dietary interventions could be necessary. Additionally,
Current Opinion in Biotechnology 2021, 70:48–55
54 Food biotechnology
combinatorial strategies, including diet, as well as live
biotherapeutic supplements could be developed in order
to restore a health-promoting microbiome in older people.
Alternative dietary regimes like the KetoDiet have also
shown a negative association with inflammation
(Figure 3b), and can, in future, be explored as alternative
dietary intervention strategies.
Conflict of interest statement
Nothing declared.
Acknowledgements
The authors are funded in part by Science Foundation Ireland (APC/SFI/
12/RC/2273) in the form of a research centre, APC Microbiome Ireland, and
by the Department of Agriculture, Food and Marine (FIRM award to the
IMMUNOMET project).
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