Calorie Restriction as a Way to Slow Harmful Age-Related Changes in the Gut Microbiome

The practice of calorie restriction, eating 20-40% fewer calories while still obtaining an optimal intake of micronutrients, produces sweeping changes in the operation of cellular metabolism. It improves health and extends life span in near all species tested to date, though much more so in short-lived species than in long-lived species. The most important mechanism appears to be a boost to the operation of the cellular housekeeping processes of autophagy, more efficiently clearing out damaged components and unwanted molecular waste before they can cause further issues. That said, near every measure of aging is slowed by calorie restriction, so it is no surprise to see in today's open access paper that this slowing also applies to the detrimental changes to the microbial populations of the gut that are observed to take place with age.

In recent years the research community has been giving ever more attention to the gut microbiome in the context of long-term health and aging. Gut microbes produce a number of compounds that are beneficial, such as tryptophan, indole, butyrate, and propionate, but this production falls off in adult life and into old age. Populations of beneficial bacterial species are replaced by populations of harmful species that interact with tissues and the immune system to cause chronic inflammation. There are many possible contributing causes for age-related changes microbial populations in the gut, such as specific dietary changes, as well as failure of the immune system to control harmful populations. It isn't clear as to which of these are more or less important, however.

While calorie restriction seems to slow this progression, and here again it is hard to say which of the possible mechanisms are the important ones, transplantation of gut microbes appears to be a better approach, one capable of reversing age-related changes. This has been demonstrated with fecal microbiota transplants from young animals to old animals, and this form of treatment is well proven in humans as a therapy for a range of conditions in which the gut is colonized by pathological microbes. It has also been trialed for a range of medical conditions that are suspected to have some inflammatory or other contribution arising from gut microbes, such as Parkinson's disease. So why not the condition of aging as well?

Calorie restriction slows age-related microbiota changes in an Alzheimer's disease model in female mice

The gut-brain axis is an integrated network in which the microbiota and central nervous system communicate via endocrine, immune, and neural signaling pathways. Several translational studies show that transferring microbiota from patients with neurodevelopmental and neurological disorders including autism, multiple sclerosis, and Parkinson's disease can influence behavior, motor dysfunction, and immune responses in relevant animal models. These studies provide evidence that intestinal microbiota may play an etiologic role in diseases that emerge at differing points during the lifespan. Consistent with this notion, Alzheimer's disease (AD) patients have altered gut microbiota compared to age-matched healthy subjects. In established animal models of AD, depleting the microbiota either in germ-free or antibiotic-treated mice served as protection against the pathological hallmark amyloid-beta (Aβ) plaque deposition.

While host genotypes influence AD risk, the most important risk factor is advanced age. In older adults, the microbiota is less diverse, and immunosenescence and age-related changes in host physiology can destabilize the microbiota. An 'aged' microbiota promotes immune dysfunction, including increased systemic inflammation and impaired macrophage phagocytosis, which can be partially restored by transferring microbiota from young to aged mice. Thus, understanding how to slow or reverse age-related changes in the gut microbiota has therapeutic implications for age-related brain diseases, including AD.

Diet is a major environmental factor that modulates the microbiota and has been proposed to prevent age-related changes of the microbiota. Calorie restriction (CR), characterized by 20-40% reduction of total calorie intake without malnutrition, increases the healthspan and lifespan in multiple model organisms. A 30% reduction in calories from carbohydrates activates neuroprotective signatures and suppresses age-related transcriptional changes in the hippocampus in wildtype (WT) mice. In the context of AD, we found that CR prevents Aβ plaque accumulation and modulates the expression of the gamma-secretase complex, the amyloid-beta precursor protein (APP) processing enzymes, in a sex-dependent manner in Tg2576 mice. In addition to effects on host physiology, CR modulates the microbiota and increases abundances of bacteria that positively correlate with lifespan. However, the association between CR, the microbiome, and AD pathogenesis has not been established.

In this study, we investigated the effect of long-term 30% CR compared with ad libitum (AL) feeding on the microbiome in aging. We studied the Tg2576 model, where a mutant variant of the human APP is expressed in transgenic mice. This transgene results in cerebral amyloid accumulation, synaptic loss, and cognitive impairment by 12 months of age. We found that female Tg2576 mice have more substantial age-related microbiome changes compared to wildtype (WT) mice, including an increase in Bacteroides, which were normalized by CR. Specific gut microbiota changes were linked to Aβ levels, with greater effects in females than in males. In the gut, Tg2576 female mice had an enhanced intestinal inflammatory transcriptional profile, which was reversed by CR. Furthermore, we demonstrate that Bacteroides colonization exacerbates Aβ deposition, which may be a mechanism whereby the gut impacts AD pathogenesis. These results suggest that long-term CR may alter the gut environment and prevent the expansion of microbes that contribute to age-related cognitive decline.