Preserving Health and Achieving Longevity
Through Caloric Restriction and Symbiotic
Equilibrium with Gut Microbiome
Department of Medicine, Hindu Rao Hospital and NDMC Medical College, India
Submission: January 06, 2019; Published: April 09, 2019
*Corresponding author: Vinod Nikhra, Department of Medicine, Hindu Rao Hospital and NDMC Medical College, New Delhi, India
How to cite this article: Vinod N. Preserving Health and Achieving Longevity Through Caloric Restriction and Symbiotic Equilibrium with Gut Microbiome. Curr Trends Biomedical Eng & Biosci. 2019; 19(1): 556003. DOI: 10.19080/CTBEB.2019.19.556003
The prolongation of life span achieved in recent decades is triumph of modern medicine. The lead challenge now is to promote healthy lifespan along with reducing incidence and severity of chronic and degenerative diseases, and the morbid frailty associated with later years. The host-microbiota interactions can be viewed in the broader context of genetic and epigenetic concepts. The lifestyle changes including dietary alterations accompanying aging have impact on gut microbiota and the activity of the innate immune system, intern, is influenced by gut microbiota. The gut microbiota also modulates cardiometabolic and inflammatory processes, thus influencing aging process.
Caloric Restriction and Gut Microbiome
There is evidence that optimal CR along with adequate nutrition can reduce adiposity, chronic inflammation and insulin resistance, and promote health and quality of life along with satisfactory level of activity of daily living (ADL) in older adults. Further, as documented by recent research, the loss of gut microbiota diversity occurs during later years and modulates aging process adversely. The loss of core microbiota diversity with advancing age, has been associated with increased frailty and degenerative diseases along with cognitive decline.
Gut Microbiota and Immunosenescence
Diet-microbiota-health interactions and the lifestyle changes including dietary alterations accompanying aging have impact on gut microbiota. Since the gut microbiota modulates cardiometabolic and immunological processes, the microbiota alterations with aging mean that older adults may experience accelerated aging-related health loss. Further, the age-associated alterations in composition, diversity and functional aspects of gut microbiota have been related to age-associated decline in immune system functioning (immunosenescence) and low-grade chronic inflammation (inflam-aging), which accompany various aging-associated pathologies.
Conclusion-Scope of Interventions
The gut microbiota has crucial impact on aging process, and as documented by recent studies the microbiota-targeted interventions for normalization of gut microbiota may have health-span-promoting effects. The CR with adequate nutrition and microbiota-targeted dietary and probiotic, prebiotic and symbiotic interventions are likely to favourably modulate the host health and aging process by enhancement of antioxidant activity, suppression of chronic inflammation and improvement of immune homeostasis and cardiometabolic profile.
The human gut is inhabited by over 100 trillion microbes of about 1000 species. These microbes have co-evolved with humans over millennia and live together in symbiotic state. The most populous bacterial phyla are Bacteroidetes and Firmicutes, constituting more than 90% of the gut microbiota, and various species in lower abundance constitute the remainder. The gut microbiota is a complex community of bacteria residing in the
GIT, the bacterial load is low in the stomach and increases expo
nentially from the duodenum, the jejunum, and the ileum, to the colon, harbouring about 109-1013 bacteria .
The gut microbiota encodes over 150 times more genes than the human genome and influences the host physiology and homeostasis, in addition providing numerous metabolites for maintenance of intestinal and general health. The activity of the innate immune system is also influenced by various subgroups of gut microbiota. This dynamic population of millions of microbes is called microbiome, having almost 10 bacterial cells for every one of human cells, which together form the meta-organism.
The lifestyle changes including dietary alterations accompanying
aging have impact on gut microbiota. The alterations in gut
microbiota, which modulates cardiometabolic and inflammatory
processes, the alterations with aging mean loss of various physiological
functions leading to accelerated aging-related health
loss in older adults. There occur changes in core microbiota taxa
leading to low microbial diversity and gut dysbiosis. Though,
the core microbiota may decline and be supplemented by other
abundant species, the full core microbiota is rarely lost (Figure
These changes lead to increase in inflammatory markers
and oxidant injury, lead to intestinal inflammation and insulin
distance (IR), precipitating T2DM and metabolic syndrome. The
group of organisms that are mostly affected by aging, are the diversity-
associated taxa, comprising of Privately and associated
genera . Further, the extreme-aged older adults (centenarians)
have a microbiota different from that in older adults .
However, several specific co-abundant taxa seem to be associated
with old age and malnutrition.
The potential for the gut microbiota to affect health has a
particular relevance for older adults. The age-associated loss of
diversity in the core microbiota groups is associated with changes
in innate immunity, sarcopenia and cognitive function, bringing-
about increased frailty and reduced cognitive performance
with aging. There is no threshold of age at which the composition
of the microbiota alters; rather, the changes occur gradually.
Thus, the gut microbiota of older adults differs from that
of younger adults. Further, the degree of retention of the core
microbiome is associated with age, general health and care, and
dietary factors .
As established by several recent studies, the gut microbiota
has a crucial impact on the aging process, and, the microbiota-
targeted interventions for normalization of gut microbiota
may have health and lifespan-promoting effects. The host-microbiota
interactions can be viewed in a broader context of genetic
and epigenetic concepts. It depends on the host nutrient signalling
pathways for its effects on host health and lifespan. The
inter-relationship of microbiome and human body is complex,
the genomes within the meta-organism interact and affect one
another and have impact on human physiology and homeostasis.
The influence of gut microflora on host health comprises of two
extremes of the relationship: symbiosis and pathogenesis.
The most of gut microbes are commensal, i.e., neutral, and
genomic sequencing have led to characterization of the diverse
commensal bacteria, comprising the metagenome - the ensemble
of host and microbiota DNA, and by extension the meta-transcriptome,
proteome and metabolome. Further, the microbiota
extends its effects beyond host pathophysiology, to modulation
of the aging process . The gut microbiota shows a wide inter-
individual variation, but intra-individually, it is relatively
stable over time . There is a functional core microbiome, provided
by the abundant bacterial taxa which is common to human
hosts regardless of age, gender and geographic location.
There is an inter-individual variation in the gut microbiota
profile, but major constituent microbes are common. The core
microbiome consists of regularly present taxa - the enterotypes
made up of 3 distinct microbial metagenomic clusters being Bacteroide,
Prevotellaceae and Firmicutes (Ruminococcaceae and
Lachnospiraceae). With age, the gut microbiota becomes diverse
and variable, simultaneously certain groups of bacteria associated
with frailty increase. The gut microbiome communicates with
the host through various biomolecules, nutrient signaling-independent
pathways, and epigenetic mechanisms. Disturbance of
these communications associated with age-related gut dysbiosis
can affect the host health and lifespan. The gut dysbiosis disrupts
the symbiosis and interdependence and triggers the innate
immune response and chronic low-grade inflammation, leading
to suboptimal aging, age-related frailty and chronic degenerative
With the age the composition of microbiota changes due
to senescence of the gut and risk factors including the altered
physiological environment with age, the lifestyle factors and diet
playing a major role (Figure 2). With aging, there is often reduction
in amount of food and associated malnutrition . There is
decrease in variety of fibre-containing foods consumption leading
to a decrease in microbiota diversity particularly with the
abundant Clostridial subpopulation . The core microbiota decreases
in abundance with aging, its loss playing a crucial role in
the aging process . The studies in fruit fly, Drosophila melanogaster,
have documented the correlation between composition
of food intake and diversity of the microbiota .
The microbiota composition alters, becoming less diverse
and more instable over time in the older adults . Further,microbiota alterations and greater than normal loss of gut microbiota
diversity, occurring with aging entail that older adults
experience accelerated aging and age-related health loss and
frailty. The loss of Clostridial subpopulation is also significantly
associated with increased frailty. After an initial change, microbial
diversity tends to recover among people living in the community
and less well in those in long-stay residential care .
The extreme-aged older adults (centenarians), in general,
have an overall decline in microbiome function parallel with various
alterations in the loss of physiological functions . With
longevity, in centenarians, there occurs enrichment of subdominant
taxa. The longevity adaptation seems to involve enrichment
in health-associated gut bacteria . Centenarians are a model
for healthy aging because they have reached the extreme limit of
life by escaping, surviving, or delaying chronic diseases. The gut
microbiota in centenarians differs from that in older adults .
Once established early in life around 3 years of age, gradually
after birth, the human gut microbiota is stably maintained
depending on the host’s dietary and health conditions. Its communication
with the host systems, microbiota-host crosstalk’s,
involves various signaling networks and their mediators. In addition,
the gut-brain axis connects gut microbiome with the central
nervous system via neurons, hormones or cytokines.
The cumulative abundance of core microbiota consisting of
symbiotic bacterial taxa (mostly belonging to Ruminococcaceae,
Lachnospiraceae, and Bacteroidaceaefamilies families), decreases
with age, and there occurs an increasing abundance of subdominant
species, as well as a rearrangement. These features
are maintained during longevity and extreme longevity, when
certain opportunistic and allochthonous bacteria such as Akarnania,
Bifidobacterium and Christensenellaceae turn into commensal
and support health. These bacterial taxa then become involved
in establishing of a new homeostasis with the aging host
and contribute in aging-associated alterations in composition,
diversity and functional attributes of gut microbiota . The
age-related decline in immune system functioning (immunosenescence)
and a low-grade chronic inflammation (inflam-aging),
may accompany aging. Because of its impact on human physiology,
metabolism and immunity, the gut microbiome is a potential
determinant of healthy aging . Indeed, the preservation of
host-microbes homeostasis can counteract inflam-aging, intestinal
permeability, and decline in muscle and bone mass and cognitive
The simpler organisms, fruit fly (D. melanogaster) and the
nematode worm (Caenorhabditis elegans) also live in the presence
of microbiota both in wild and lab habitat, like other more
complex organisms. Due to their genetic tractability and short
lifespans, the studies allow to document the effect of microbiota
on genetic pathways modulating the aging process. The host and
bacteria interactions, thus, extend beyond intestinal homeostasis
to influence systemic health and longevity.
C. elegans are grown in co-culture with non-pathogenic
strains of E. coli ‘OP50’ bacteria, which provides essential nutrients
and components to it. The non-pathogenic, E. coli OP50
proliferate inside older animals and suppresses infection and
increases worm lifespan . In young worms however, E. coli
are mechanically broken down before entering the gut and do
not live in the animal as a true microbiome. Beyond their role as
a nutrient source, E. coli secrete diffusible molecules, including
metabolites and small RNAs that can directly impact C. elegans
aging. C. elegans cannot produce their own NO since they lack
The worms have been shown to utilize NO produced from
the bacteria within their microenvironment and the bacterial
NO modulates C. elegans lifespan via effects on host transcription
. Bacterial-derived signals NO and ncRNAs regulate C.
elegans longevity. E. coli modulate longevity of the worm by using
the innate RNAi machinery, as the worm incapable of RNAi
are resistant to the effects of Dra. Metformin increases C. elegans
lifespan via effects on bacterial folate metabolism: Feeding
worms metformin robustly increases lifespan in an AMPK-dependent
manner. This response is indirectly mediated by the
effect of the drug on bacteria, rather than the worms themselves.
Metformin suppresses folate metabolism specifically in E.
coli, and feeding worms increases lifespan. Reduced folate metabolism
decreases methionine content of bacteria, and this
effect is causal to metformin-induced longevity in C. elegans. L.
plantarum drive Drosophila growth under low nutrient conditions
via the longevity modulator TOR. The bacteria also affect
the capacity of flies to sense nutrients. The presence of microbiota
at the interface of the gut epithelium also has systemic effects
on host aging. The PGRP-SC2 overexpression in Drosophila ECs
significantly increases lifespan dependent upon the presence of
commensal bacteria in the gut. The reduced dietary methionine
has been shown to promote longevity in both Drosophila and rodents.
Metformin decreases folate levels in humans, as well.
In general, there occurs compositional change in the functional
core microbiome and/or the enrichment of non-core
functions with advancing age . In fact, the changes in composition
of gut microbiota and gut microbial diversity inversely
correlates with biological age or functional age and are independent
of chronological age. The gut microbiota of the elderly
becomes more diverse and variable with advancing age and the
three main bacterial taxa in the core microbiota, become less
abundant in older age groups, while certain health-associated
species become more abundant in older age groups including
centenarians and semi-supercentenarians. In general, the Ruminococcin
and Corbeilles (Firmicutes phylum), and Egger Thella
(Actinobacteria) genera becomes abundant, the overall gut microbiota richness decreases, while some microbial taxa associated
with unhealthy aging emerge with increase in biological age.
The gut dysbiosis is the disruption of the commensal homeostasis
between the host and gut microbiota due either altered
host factors or microbial composition or both. The factors
contributing to gut dysbiosis include unbalanced diet, environmental
toxins, drugs, ROS, psychological stressors and various
proinflammatory conditions. Gut dysbiosis due to antibiotics or
high-fat or carbohydrate intake is associated with obesity and
metabolic disorders. In turn, the gut dysbiosis has been associated
with disorders like inflammatory bowel disease, obesity, diabetes,
cardiovascular diseases and neurodegenerative diseases.
The altered innate immune response caused by dysbiosis, in the
aging gut provokes chronic inflammation and oxidative injury
leading to gut dysplasia and defective epithelial functioning, and
accelerated aging and increased mortality.
With advancing chronological age, the homeostatic relationship
between the gut microbiota and the host deteriorates
along with gut dysbiosis and the gut microbiota becomes more
diverse with phylogenetic richness. The dysbiosis changes in the
aging gut provoke oxidative stress and proinflammatory changes
with altered innate immunity. In addition, the gut dysbiosis disturbs
communication between the gut ¬microbiota and the host
through various biomolecules, CR-independent signaling pathways
and epigenetic mechanisms, promotes proinflammatory
immune responses and chronic degenerative reactions affecting
the host health and longevity.
There is an evidence from the research that the chronic,
age-related inflammation called inflam-aging is brought about
by senescent cells, cell debris immunosenescence and microbial
burden. Thus, the age-associated changes in intestinal microbiota
and their bidirectional relationship with the host, bring about
chronic inflammation. The gut microbiome appears to play a key
role in age-related inflammation . With the advanced age,
the ability to resolve inflammation becomes impaired leading to
sustained tissue infiltration by leukocytes and chronic release of
pro-inflammatory cytokines and chemokines.
The most important factor associated with age-related inflammation
is decrease in the efficiency of the immune system,
i.e., immuno-senescence, characterized by thymus atrophy, reductions
in neutrophil function, naïve T cell number, and the
cytotoxic capacity of natural killer cells, and lowered B-cell
antibody production in response to antigen. The cause of immune-
senescence is thought to be that the chronic lifetime antigenic
burden exhausts finite capacity of the organism’s immune
system, leading to long-term risks of chronic inflammation and
disease. The gut microbiome appears to play an integral role in
these age-related inflammatory changes. The advanced age is associated
with changes in microbiota composition characterized
by a loss of diversity in the core taxa associated with key geriatric
syndromes including physical frailty and cognitive decline.
The research studies in invertebrate and vertebrate species
have led to understanding of various aspects of the pathophysiology
of gut dysbiosis. Through the loss of gut microbial richness
and altered microbiome composition, dysbiosis has been documented
to play a significant role in accelerated aging process
and negative impact on longevity.
1. In the African turquoise killifish, loss of the gut
microbial richness occurs with aging. By treating the middleaged
killifish with antibiotics to prevent the age-related gut
dysbiosis and with intestinal contents from the young fish, Smith
et al were able to show significant lifespan extension. Further,
the long-lived recipient fish maintained higher mobility and
microbial diversity compared with controls .
2. In Drosophila, there is increased number of gut
microbes in older flies. The gut dysbiosis triggers intestine
epithelial dysplasia and altered innate immune response in
aging flies and leads to increased mortality .
3. The mice studies also confirm the causative role of gut
dysbiosis in innate-immunity-induced inflammation.
Transfer of the gut microbiota from old mice to young germfree
mice triggers altered innate immunity and inflammatory
response mimicking “inflam-aging” .
The commensal microbes produce numerous biomolecules
endogenously by in the digestive tract, which modulate health
and aging process. These include various vitamins, fermentation
products, gut-derived hormones and bio-compounds relevant to
the neurological health.
1. Rapamycin is an immunosuppressant produced by soil
bacteria which binds to immunophilin, an FK binding protein,
and the complex inhibits mTOR function. In mice, it alters the
host gene expression profiles as well as the gut metagenomes.
The FOXO, regulating expression of various proteins, is an important
factor for aging process and lifespan. The inactivation
of FOXO as well as its chronic activation shortens lifespan, the
overall effect being the net effect of all the positive and negative
effects combined. Thus, chronic activation of IMD/Relish or inactivation
of dual oxidase results in shortened lifespan in fruit flies.
2. Metformin is a compound of exogenous origin. In C.
elegans, excessive folate limits lifespan and metformin extends
lifespan through inhibition of bacterial folate and methionine
3. Nitric oxide (NO) is a signaling molecule involved in
many physiological functions. C. elegans cannot produce NO due to lack of the NO synthase. NO provided either by gut bacteria or
by exogenous supplementation increases lifespan.
4. Colonic acid, an exopolysaccharide, promotes mitochondrial
fission and enhances the mitochondrial unfolded protein
response under stressful conditions. The beneficial effects
of colonic acid are independent of the CR signaling pathways. It
extends lifespan in C. elegans and D. melanogaster.
5. Short-chain fatty acids (SCFAs) are fermentation products
of dietary fibers by the anaerobic gut microbiota, which
enter the circulation from the gut and have certain beneficial
roles in energy metabolism. Acetate reduces serum cholesterol
and triglyceride levels, propionate lowers glucose levels, and
butyrate improves insulin sensitivity. There occurs age-related
decline in the concerned genes and in SCFAs production, which
has been associated with frailty.
SCFAs have both negative and positive effects on health, in a
dose dependent manner. Some SCFAs are the main causal factor
for the α-synuclein-related pathology caused by the gut microbiota.
In the mouse model of Parkinson’s disease, α-synuclein aggregates
activate immune cells, including phagocytic microglial
cells in the CNS and treatment of germ-free mice overexpressing
α-synuclein with a mixture of acetate, propionate and butyrate
leads to neuroinflammation and motor deficits .
Another SCFA, butyrate inhibits histone deacetylases
(HDACs) and has a profound effect on the host epigenome and
aging process. The inhibition of HDACs by butyrate promotes
histone lysine acetylation, leading to an open chromatin state
and transcription activation. Butyrate increases lifespan in Drosophila.
In aging mice, butyrate counters muscle atrophy and
enhances memory functioning . The activation of FOXO by
HDACs can cause skeletal muscle atrophy in mice via autophagy,
and inactivation of HDAC by butyrate can reverse the atrophy.
The gut microbiota is also causally linked to the development
of neurodegenerative disorders . The enteroendocrine cells
in gut epithelium express α-synuclein, which is close to α-synuclein-
containing enteric neurons, prompting the hypothesis that
α-synuclein originates from the gut and spreads to the central
nervous system and may be causative for Parkinson’s disease
. Cerebral deposition of Aβ plaques is a critical risk factor for
various types of dementia, including Alzheimer’s disease. The
causative role of the gut dysbiosis in Alzheimer’s disease has
Transgenic mice expressing Aβ precursor protein start to
accumulate cerebral Aβ early on, and their gut microbiota composition
differs greatly compared with that of the non-transgenic
littermates. Transgenic mice rendered germ free show lower
Aβ levels and significantly reduced cerebral Aβ deposition compared
with conventionally reared transgenic mice. Furthermore,
transfer of the gut microbiota from conventionally reared transgenic
mice to germ-free transgenic mice was more effective in
the induction of Aβ pathology. These observations indicate the
role of the gut brain axis in development of neurodegenerative
An enormous portion of immune system is involved for maintaining
homeostasis with the microbiota and about 70% of the
total lymphocytes reside in the gut-associated lymphoid tissue.
Further, the gut microbiota is significantly involved in various inflammatory
responses and is an important regulator of immunity
including tolerance. The microbiota suppresses inflammatory
responses to food and other orally ingested antigens and play a
protective role against inflammatory responses through toll-like
receptor (TLR) activation to promote tissue repair and survival.
The immune cells also regulate inflammation and allergic reactions
through recognition of SCFAs produced via bacterial breakdown
of indigestible dietary components such as fibre.
Though the human ageing process is associated with gradual
declines in functions across almost all organs, the bacterial
organisms in the gut do not age per se. However, due to various
age-related functional alterations, the older adult manifest
changes in lifestyle patterns, diet and other gut-related physiological
functions influencing the gut microbiota composition
and stability. The high-fat diet can potentially alter gut bacteria
and leads to dysbiosis, which contributes to increased gut permeability
and metabolic endotoxemia, contributes to low-grade
inflammation and insulin resistance and diabetes, adiposity and
other metabolic disorders (Figure 3).
Gut dysbiosis and physical frailty: The recent research
suggests that the gut microbiome plays a significant role in
age-associated physical frailty in older adults . The age-related
dietary changes also appear to contribute to the dysbiosis.
Advanced age associated with deterioration in nutrient intake
and absorption including dentition, sensory changes like taste
and smell, salivary function, digestion, and intestinal transit
time also contribute to dysbiosis. The host factors like unhealthy
diet and use of medications, especially antibiotics, have impact
on the gut microbiota composition and function and contribute to gut dysbiosis, a state of disrupted homeostasis of the gut
microbiome, which leads to increased IR and may manifest as
adiposity and T2DM [31,32]. Further, adiposity and T2DM are
associated with an altered gut microbiota, inflammation, and gut
Gut dysbiosis and immunity: The changes in gut microbial
diversity and density leading to dysbiosis have been shown to
have impact on immunity leading to chronic inflammation, even
in the distal organs. The failure to regulate the inflammatory responses
is a contributor to the development of various chronic
inflammatory and degenerative disorders affecting the gut and
other organs including the central nervous system and contributes
to age-related cognitive decline. The brain amyloid content
and circulating inflammatory analytes have been associated
with the inflammatory bacteria taxon Escherichia/Shigella and
inversely associated with the anti-inflammatory E. rectal taxon.
A recent study has linked brain amyloidosis and chronic inflammation
among cognitively impaired elders with the abundance
of pro- and anti-inflammatory gut microbiota .
There appears to exist a gut microbiota signature that promotes
intestinal inflammation and subsequent systemic lowgrade
inflammation, which in turn promotes the development
of T2DM . The animal studies have also endorsed that shifts
in the composition of the gut microbiome influence metabolism
and energy balance, and the chronic inflammation and increased
gut permeability may play a significant role in development of
adiposity and T2DM . The immune system is brought up by
commensal bacteria, especially bacteria in the gut. Homeostasis
of the gut microbiota is important in modulation of the host immunity
and control of inflammation .
The fallouts of gut dysbiosis: The gut microbiota-derived
metabolites, lipopolysaccharides (LPSs) and SCFAs have impact
on IR and adipogenesis [37,38]. LPSs cause low-grade inflammation
through the induction of inflammatory cytokines by
immune cells and adipocytes. Whereas SCFAs, which are end
products of the microbial fermentation of macronutrients such
as acetate and butyrate, modulate gene expression and reduce
chemokine and proinflammatory cytokine production by monocytes,
acting on intestinal tissue immune cells locally as well as
systemically. The high-calorie diets contribute to obesity and
T2DM, and there appears to exist a link between diet, obesity
and the gut microbiota.
The studies in mice have demonstrated that a high-fat diet
(over 60% calories derived from fat) decreases the gur microbial
diversity. In an important study, Le Chatelier et al documented
that the diversity of human gut microbiome correlated with IR,
fatty liver and increased C-reactive protein and leptin concentrations
and decreased serum adiponectin concentrations in both
nonobese and obese Danish individuals .
The age-related changes in microbiome, the increased use of
medications including antibiotics and consumption of high-saturated
fat and high-sugar diet appears to contribute to the depletion
of certain beneficial components of the microbiome .
This, in turn, leads to to chronic activation of the immune system,
altered immunity due to chronic activation of innate and
adaptive immune systems. The increased intestinal permeability
is associated with IBDs and other disorders linked with the gutbrain
Gut dysbiosis - Changes with age: There occur changes in
the intestinal epithelial barrier with age . The gut barrier
and nutrient transport functions decline with aging, and dysbiosis
weakens the intestinal barrier function. In the Irish ELDERMET
cohort study, there has been documented alterations in the
core microbiota of those over 65 years of age, characterized by
a greater proportion of Bacteroides spp. and distinct abundance
patterns of Clostridium groups compared to younger individuals
. The older individuals also display a loss of diversity-associated
taxa, including Privately and associated genera, contributing
to instability in the microbiome composition. In another
study, Biaggio et al. reported that a group of centenarians from
Northern Italy displayed low species diversity compared to
younger adults ~30 years of age. The specific changes occur
within Firmicutes (one of the two dominant phyla in the gut)
subgroups and enrichment of Proteobacteria - an opportunistic,
which can overtake commensal bacteria and induce pathology.
These microbiome changes are also accompanied by loss of
genes for SCFAs production and decreased saccharolytic potential,
while proteolytic functions become more abundant compared
to the intestinal metagenome of younger adults . Further,
these changes in microbiota are associated with increased
plasma concentrations of inflammatory cytokines IL-6 and IL-8.
These observations are supported by the studies in Drosophila,
documenting that age-related changes potentiate chronic inflammation
and increased intestinal permeability . The mice
studies by Devarajan et al, also support this hypothesis . In
the study, the germ-free mice did not display an age-related increase
in systemic pro-inflammatory cytokines, but co-housing
germ-free with old and conventionally raised mice increased circulating
pro-inflammatory cytokines. Further, anti-TNF therapy
reversed age-related microbial changes.
The scope of interventions: As documented by recent studies,
the gut microbiota has a crucial impact on the health and
aging process. Further, the microbiota-targeted interventions
for normalization of gut microbiota and restoration of symbiosis
appear to have potential health-span-promoting effects .
The successful execution of the targeted interventions for normalization
of gut microbiota needs Diagnostic tests, followed by
nutritional therapy and microbial modulation, followed by the
post-therapy assessment (Figure 4).
The microbiome-based diagnostic tests should be followed
by lifestyle changes including exercise and upgradation of activity
level and dietary modifications by planning a balanced diet
rich in functional foods and adding nutraceuticals. The measures
for the gut microbial modulation by prebiotics, probiotics and
symbiotic, should be followed by the post-microbial therapy assessment,
and suitable action thereafter. The normalization of
gut microbiota and restoration of symbiosis between microbiome
and the host is a continuous endeavour for health and longevity.
The microbiota-targeted interventions, thus, appear to be a
promising health-preserving, anti-aging treatment plan (Figure
5). Various health-span-promoting interventions include both
prophylactic and therapeutic modalities to decrease oxidative
injury, to curtail chronic intestinal inflammation, improve gut
dysbiosis and insulin resistance and its fallouts, and for normalization
gut microbiota to restore symbiotic relationship with the
Potential intervention strategies: The microbiota-targeted
dietary and probiotic interventions (Figure 6) have been
shown to favourably affect the host health and aging by an enhancement
of antioxidant activity, improving immune homeostasis,
suppression of chronic inflammation, regulation of fat
deposition and metabolism and prevention of insulin resistance
. Certain simple measures to support the gut microbiota include
- the dietary intake of local, seasonal vegetables and fresh
fruits, and organic foods, along with a fair portion of healthy fats.
This should be accompanied with along intake of probiotic
and prebiotic-rich diet containing plain yogurt, aged cheeses
and fermented foods such as kimchi, and avoiding exposure to
antibiotics and unnecessary medication including laxatives. Further,
there are potential benefits from nutritional supplements
like coffee, resveratrol and quercetin and other flavonoids. Similarly,
the Mediterranean diet hold promises for balancing the gut
It appears that interventions designed to target the gut
microbiome may be capable of producing beneficial effects on
age-related chronic inflammation and gut dysbiosis, and overall
health. Some of the promising strategies having beneficial effects
on the gut microbiome are:
I. Nutrition and lifestyle factors: The gut barrier and
nutrient transport functions decline with aging and microbial
dysbiosis adversely affects the intestinal barrier function. In addition,
nutrition is the major factor affecting the gut microbiota
as well as influencing the host’s epigenetic milieu. The nutrition
derived factors such as folate and choline, as dietary methyl-donors,
influence DNA methylation and the nutrient-signaling
The high-fat diet appears to be one of the driving factors
for gut dysbiosis, inversely the diet low in fat content is helpful
(Figure 7). The moderate reduction in calorie intake, i.e., caloric
restriction (CR) potentially improves health and extend lifespan
through certain evolutionarily conserved biological pathways.
The reduced nutrient availability, brought about by CR, decreases
AKT (protein kinase B) activity resulting in enhanced
FOXO (Forehead box O transcription factor) activity. Inversely,
the activation of AKT by nutrient abundance leads to the inactivation of FOXO, a major factor for inducing expression of various
pathways involved in cell metabolism, autophagy and stress-response,
an essential link to longer lifespan .
The gut-specific FKH, a homolog of Forehead box A (FOXA)
upregulation has been shown to improve gut barrier function
and expression of nutrient transporters, which help to increase
lifespan. The Physical exercise and increase in activity of daily
living (ADL) is clinically recommended intervention having
important benefits on the gut physiology and microbiota .
The aerobic exercise enhances epithelial membrane integrity,
improves microbial diversity and attenuates intestinal inflammation.
II. Probiotic-rich and Fermented foods: Interventional
studies show that dietary changes result in substantial and rapid
changes in the make-up of the gut microbiome . The deprivation
of fermented foods in diet causes a fall in innate immune
response, including decreased phagocytosis by leukocytes and
immune response against infections . The consumption of
probiotic bacteria such as those found in yogurt and other fermented
milk products have beneficial effect on composition of
the gut microbiome .
The dietary supplementation with probiotics is one of the
most promising interventions for re-balancing the gut microbiome.
Supplementing with probiotics supports the gut microbiome
and help in repopulating gut with beneficial bacteria. The
well-known actions of probiotics include antimicrobial activity,
improved gut microflora composition, enhancement of intestinal
barrier function and immunomodulation. A study in mice has reported
that probiotic supplementation with Lactobacillus plantarum
WCFS1 prevented age-related decline in the colon mucus
barrier in a mouse model of accelerated aging . The probiotics
have anti-inflammatory properties and can also be utilized as
a vehicle to deliver other therapeutic compounds .
III. Fecal microbe transplantation: Recently, a high effectiveness
and safety of novel therapeutic application such as fecal
microbiota transplantation in the prevention and treatment of
age-related pathological conditions including atherosclerosis,
T2DM and Parkinson’s disease has been demonstrated.
IV. Others: Metformin prevents the overproduction of glucose
by hepatocytes, it delays glucose absorption during digestion
after a meal. The administration of metformin appears to
alter the composition of the microbiota. It increases abundance
of mucin-degrading bacterium Akarnania in the obese mice. A
recent study in human volunteers has confirmed the effect of
metformin on the gut microbiota.
Modification of gustatory or olfactory neurons, apart from
nutrient availability, the has been shown to modulate lifespan
in Caenorhabditis elegans and Drosophila melanogaster. Studies
support the notion that gastric bypass surgery leads to a
substantial shift in the gut microbiota, which may contribute to
Treatments for chronic inflammation appears to be a promising
strategy for healthy aging. The gut microbiome may represent
a novel site of intervention for the prevention and treatment
of late-life inflammation. A variety of biological, medical
and lifestyle factors appear to contribute to gut dysbiosis in
late-life, and interventions specifically designed to target these
factors may be useful in restoring microbial balance and attenuating
inflammation. The healthy aging is dependent not only on
genetics, lifestyle choices and a positive attitude, but also another
fast emerging factor, the gut microbiome. The latter plays a
significant larger role in staying healthy in older adults. Further,
In one of the largest studies on human gut microbiota, has documented
that the composition of the gut microbiome of healthy
older adults was essentially similar to that of healthy younger
people [54-56]. But, the gut microbiomes of the elderly have
several characteristics, including instability among gut bacterial
species counts and reduction in bacterial diversity .
The unbalanced microbiome appears to be related to various
harmful alterations in health, whereas the healthy older adults
and elderly (up to 90 years of age) have the rich and thriving
microbiome similar to younger people who are about 30 years
old. The studies reinforce the importance of balanced microbial
diversity for health and that some of the unavoidable consequences
of aging might be the reversible effects of an unbalanced
microbiome. Further, various studies have shown that it
may be possible to reset the microbiome to that of a younger and
The composition of gut microbiome naturally shifts over
time and swings towards having more Bifidobacterial with aging.
This natural phenomenon, however, is hampered by a diet high
in processed food and low in prebiotic fibres, bouts of stress and
inactivity, exposure to antibiotics and environmental pollutants.
The Bifidobacterial plays a key role in many areas of well-being
and important for maintaining strong bones and joints, reducing
temporary bouts of inflammation, maintaining strong memory
and good mental health, promoting healthy digestion and nutrient
absorption, helping body balance energy levels, protecting
intestinal wall, and supporting the immune system. Further, having
a balanced gut microbiome with Bifidobacterial species can
control certain factors accelerating the shortening of telomeres
The gut barrier and nutrient transport functions decline
with aging, and dysbiosis weakens the intestinal barrier function.
A moderate reduction in calorie intake, i.e., caloric restriction
(CR) can potentially improve health and extend lifespan
through certain evolutionarily conserved biological pathways.
The evolutionarily conserved genes modulating aging in invertebrates
and mammals, and linked to longevity in humans, include
the insulin/IGF-1 like signaling (IIS) pathway, the target
of rapamycin (TOR) and AMP-activated protein kinase (AMPK).The reduced nutrient availability decreases AKT activity resulting
in enhanced FOXO activity. FOXO is abundantly expressed in
the C. elegans intestine, and its enhanced expression improves
Inversely, the activation of AKT (protein kinase B) by nutrient
abundance leads to the inactivation of FOXO (a Forkhead box O
transcription factor), which is a major factor to longevity, inducing
expression of various pathways involved in cell metabolism,
autophagy and stress-response. Another factor, FKH, a homolog
of Forhhead box A (FOXA), is required for the IIS. Gut-specific
FKH upregulation improves gut barrier function and expression
of nutrient transporters, which help to increase lifespan, as in
aged fruit flies.
Another nutrient signaling serine/threonine kinase pathway,
mTOR (mechanistic or mammalian target of rapamycin),
also responds to nutrients as well as certain other signals, such
as growth hormones and mitogens. The mTOR as mTORC1 and
mTORC2 (effects of mTORC1 are more extensive than mTORC2)
subunits, both regulating various cellular processes related
to cell growth, proliferation, and survival. FKH influences the
The health and lifespan extension by dietary intervention
or inhibition of TOR activity by rapamycin involves altered gut
microbiota, as shown in mice experiments. The gut microbiome
and the host nutrient signaling pathways have been shown to
be interconnected. The experiments using C. elegans and Escherichia
coli-mutants have outlined the role of host IIS/TOR pathways
for the lifespan extending effects.