The Role Of Gut Microbiota in Aging And Aging Related Neurodegenerative Disorders: Insights From Drosophila Model Part 1
Aug 22, 2024
Abstract:
Aging is characterized by a time-dependent impairment of physiological function and increased susceptibility to death. It is the major risk factor for neurodegeneration.
As people age, their organs and system function gradually decline. This aging process is inevitable and will show obvious characteristics physically and mentally. Among them, memory is also affected.
It is a natural phenomenon that memory gradually declines as people age. This memory decline may have a certain impact on daily life, such as forgetting some things and being unable to remember new information, but it does not mean that all elderly people will seriously affect their daily lives. Among the elderly, the degree and speed of memory decline depend largely on their lifestyle and personal habits. For example, whether they exercise regularly and whether they have a regular work and rest schedule. These factors will have a huge impact on memory. Therefore, we should maintain an optimistic attitude and try to maintain good living habits and regular work and rest schedule every day.
At the same time, the elderly can also improve their memory through various methods. For example, take a walk frequently, do some light exercise and sports activities, etc. These activities can stimulate blood circulation, increase the body's oxygen supply, and improve the brain's performance and memory. In addition, you can enrich your life by reading more, listening to music, traveling, etc., and promoting brain thinking and flexibility.
There are many healthy elderly people around us. Although their memory has declined, they can still face life positively and optimistically, actively participate in various activities, and enjoy the joy and happiness brought by their peak years. Memory loss does not mean the degeneration of people's spiritual life and physical health. On the contrary, it can inspire people to better cherish every moment of life. It can be seen that we need to improve memory. Cistanche can significantly improve memory because Cistanche can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.
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Neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD) are the main causes of dementia in the old population. Gut microbiota is a community of microorganisms colonized in the gastrointestinal (GI) tract.
The alteration of gut microbiota has been proven to be associated with aging and aging-related neurodegeneration. Drosophila is a powerful tool to study microbiota-mediated physiological and pathological functions.
Here, we summarize the recent advances using Drosophila as model organisms to clarify the molecular mechanisms and develop a therapeutic method targeting microbiota in aging and aging-related neurodegenerative disorders.
Keywords: aging; neurodegeneration; Drosophila; microbiota; Alzheimer's disease; Parkinson's disease.
1. Introduction
Aging is characterized by a time-dependent impairment of physiological function and increased susceptibility to death [1]. It is the major risk factor for a plethora of human diseases, including cancer, metabolic syndrome, cardiovascular disorders, and neurodegeneration.
Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), are the main causes of dementia in the elderly [2]. Gut microbiota is a community of microorganisms colonized in the gastrointestinal (GI) tract, including bacteria, viruses, protozoa, and fungi [3]. The gut microbiota contributes to development, metabolic homeostasis, and physiology [4].
Dysbiosis is defined as an imbalance of microbial communities in the GI tract and is associated with aging and aging-related neurodegeneration [5]. With a short lifespan and easy genetic manipulation, Drosophila is recognized as a powerful tool to clarify the molecular mechanisms of development and diseases.
Many mammalian tissues including the heart and kidney have equivalent parts in Drosophila, which is absent in C. elegans, another widely used model organism in aging research.
It has been found that two-thirds of human disease-associated genes and all major signaling pathways are conserved in Drosophila [6]. Insulin/IGF-1-like signaling and mechanistic Target of Rapamycin (mTOR) signaling, key pathways that control Drosophila longevity, have been proven to mediate the aging process in mammals [7].
The Drosophila microbial community is composed of 5–20 different microbial species, including the Lactobacillus, Acetobacter, Enterococcus, and Leuconostoc, which are much less complex than mammals [8].
Besides, Germ-free (GF) or gnotobiotic Drosophila is much easier to obtain and culture in large quantities. Findings from Drosophila studies on microbiota–host interaction have the potential for translating into mammals. For example, gut microbiota promotes juvenile growth conservatively in Drosophila and mice [9,10].
Monocolonized GF flies and mice with Lactobacillus plantarumWJL recapitulate the beneficial effects of the microbiota on postnatal growth [10]. These advantages make Drosophila an ideal model organism to study microbiota-mediated physiological functions in aging and molecular pathology of neurodegenerative disorders.
2. Microbiota in Aging Drosophila
2.1. Microbiota in Human Aging
The microbial organisms colonize in the GI tract after birth and Bifidobacterium genus is dominant for infants [11]. The diversity increases after the first year. The adult microbiota is dominated by Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria [12].
Aging reduces the biodiversity of human gut microbiota and the abundance of Bifidobacteria, Lactobacilli, and short-chain free fatty acids (SCFAs) producers, such as Faecalibacterium prausnitzii, Eubacterium spp., Roseburia spp., and Ruminococcus spp. [13].
Studies carried out in China and Italy separately report that microbial community richness contributes to longevity [14,15].
The shared alteration of microbiota with aging could be found in Blautia, Clostridium cluster XIVa, Faecalibacterium, Escherichia_Shigella, Lachnospiraceae, Ruminococcaceae, and Erysipelotrichaceae.
A study on three independent cohorts comprising over 9000 individuals shows that the depletion of core genera, primarily Bacteroides, is beneficial for healthy aging [16].
The gut microbiota of long-living people (aged over 90 years) has also been investigated. By metagenomic sequencing of stool samples, healthy long-living people have a higher abundance of Bacteroidetes and several functional metabolic pathways [17].
In contrast, the unhealthy long-living group contains a higher abundance of Streptococcus and more functional pathways for xenobiotics biodegradation. These reports from human studies are not very consistent due to differences in race, lifestyle, and diet. It requires further investigations using various model organisms to clarify the role of microbiota in aging.
2.2. Alteration of Microbiota in Drosophila Aging
Proteobacteria (Acetobacter and Komagataeibacter) and Firmicutes (Lactobacillus and Leuconostoc) comprise the major part of the gut microbiota in Drosophila [18].
The stomach-like copper cell region (CCR) in the middle midgut controls the distribution and composition of the microbiota [19]. The abundance and richness of the microbial species increase dramatically with age.
Acetobacter persici and Lactobacillus brevis are dominant species in young flies while Acetobacter malorum and Lactobacillus plantarum are dominant in old Drosophila [20]. Axenic flies could be obtained by embryo bleaching and culture on sterile food.
The second and third generations of axenic flies live much longer than those raised conventionally. This observation is reproduced in antibiotics-treated conventionally cultured flies.
Further experiments show that increased microbial abundance is a stronger determinant of host lifespan than microbial composition [20,21]. When germ-free (GF) adult Drosophila was inoculated with a cocktail of bacterial species, including Acetobacter pomorum, Lactobacillus plantarum, Enterococcus faecalis, Acetobacter sp., and Leuconostoc pseudomesenteroides, aging shifts the gut microbiota composition as indicated by β-Diversity and PCoA assay [22].
Absolute quantification of the total bacterial cell number by qPCR shows that bacterial load increases with age. Dietary restriction (DR) during adulthood has an evolutionary conserved anti-aging effect [23].
When subjected to a regime of 2-day fed and 5-day fasting for one month, Drosophila lifespan increases significantly. The load of bacteria decreases, and the gut barrier function is improved at day 40 post intermittent fasting treatment.
The effects of microbial organisms on Drosophila aging are not very consistent, which could be explained by several reasons. The time point for Drosophila to be colonized with microbial organisms is important for their effects on longevity.
There is a lifespan-enhancing effect for bacteria when it is delivered to axenic Drosophila during the first week of adult life [24]. However, contact with bacteria in later life reduces the survival time significantly [24].
The nutritional environment should also be considered when analyzing the role of microbiota in aging. The lifespan of Drosophila could either be extended or shortened by microbes when they are cultured under malnourished (low yeast) diets or rich (high yeast) diets [25].
Axenic Drosophila could be obtained either by egg bleaching or antibiotic treatment, which may cause toxic effects and affect the lifespan. Lee et al. report that the lifespan of axenic flies obtained by the sodium hypochlorite-based bleaching method is much shorter than conventionally reared flies [20].
However, the 2nd and 3rd generations of axenic flies after 1st generation bleaching live much longer than conventionally reared flies.
The detrimental effects could also be observed in antibiotics-treated axenic Drosophila. The diluted antibiotic cocktail with no toxic effects on axenic Drosophila prolongs the lifespan of conventionally reared flies [20].
2.3. Mechanisms of Microbiota in Drosophila Aging
Gene ontology (GO) analysis identifies aging-related major categories of gene expression in flies are immunity, olfaction/sensation, stress response, rhythmic behavior, and metabolism.
The alteration of 70% of aging-induced genes, especially for stress-resistance (Hsp70, Hsp26, and Hsp27) and activation of innate immunity (CecC, DptB, and AttA), disappears in axenic Drosophila cultured on media with antibiotics for multi-generations [21]. Accordingly, axenic flies demonstrate more resistance to oxidative stress, starvation, and challenge to Drosophila pathogen Erwinia carotovora subsp. carotovora (ATCC 15390).
In contrast, the processes of rhythmic behavior, chitin-based cuticle development, and sensory perception of smell are still enriched in aged axenic-raised flies.
In addition to the Toll signaling pathway, the Drosophila immune response is regulated by the immune deficiency (IMD) pathway, which controls the expression of several antimicrobial peptides (AMPs). Aging increases the expression of several AMPs, such as diptericin, drosocin, and attacin A, in the Drosophila gut and the whole body. These effects could be abolished by adding back of A.
acetic at adulthood, suggesting that microbiome alteration could drive IMD hyperactivation during aging. Metabolic pathways participating in the aging process are also found to be influenced by gut microbiota.
Allantoin, an end product of purine metabolism, is increased during aging. Acetobacter persici in the Drosophila gut could activate the IMD pathway in the renal tubules and promote allantoin production [26].
Metagenome-wide association (MGWA) identifies cysteine and methionine metabolism contributing to longevity in Drosophila [27]. Flies inoculated with Acetobacter labarum ectopically expressing cystathionine beta-synthase (CBS), which drives flux through transsulfuration and restricts methionine content, demonstrate improved longevity.
Compared with lifespan, health span is the length of time that an individual remains healthy without neurodegeneration and other aging-related disorders. Microbiota-derived indoles extend the health span of various organisms [28].
Germ-free Drosophila raised with K12 E. coli has improved the lifespan, climbing ability, and resistance to heat stress, which is abolished after the mutation of indole synthesis essential gene tryptophanase (tnaA).
The aryl hydrocarbon receptor (AHR) is the direct receptor for indoles. K12 E. coli could not improve the health span in AHR mutant flies, indicating the critical role of AHR in the molecular mechanism for indole in healthy aging.
These findings from Drosophila are conserved in C. elegans and mice, further proving Drosophila is a powerful tool in the research of microbiota in aging. The gut is the first barrier for microbiota and their bidirectional interaction contributes to the aging process. Alteration in the microbiota activates immune genes and precedes intestinal barrier dysfunction in aged Drosophila [29].
Following intestinal barrier disruption, microbiota composition alters dramatically and induces systemic immune activation. Lactate, produced by L. plantarum in the gut microbiota, could be oxidized into pyruvate and release NADH in the enterocyte. The NADPH oxidase Nox utilizes NADH to produce ROS and promotes intestinal stem cells (ISCs) proliferation.
Subsequent gut hyperplasia will shorten the lifespan of aged flies. Host immune dysfunction can also lead to dysbiosis that in turn promotes aging. Constitutive activation of the gut immune system by mutation of Pdm1/nubbin (nub), a POU transcriptional regulator, increased the abundance of bacteria and richness of microbiota composition [30].
The lifespan-shortening effects of nub mutation were abolished after antibiotics treatment. Peptidoglycan recognition proteins (PGRPs) are innate immunity molecules conserved from insects to mammals.
Mutation of PGRP in Drosophila leads to overgrowth of Lactobacillus plantarum and lactic acid production, which promotes Nox-mediated ROS production, intestinal damage, intestinal stem cell proliferation, and dysplasia [29].
Activation of JAK/Stat signaling in the gut induces age-related metaplasia, commensal dysbiosis, and gut functional decline, which ultimately decreases the lifespan of Drosophila [19].
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