Clarissa C. Ren

Over the past century, we have witnessed an increase in life-expectancy due to public health measures; however, we have also seen an increase in susceptibility to chronic disease and frailty. Microbiome dysfunction may be linked to many of the conditions that increase in prevalence with age, including type 2 diabetes, cardiovascular disease, Alzheimer’s disease, and cancer, suggesting the need for further research on these connections. Moreover, because both non-modifiable (e.g., age, sex, genetics) and environmental (e.g., diet, infection) factors can influence the microbiome, there are vast opportunities for the use of interventions related to the microbiome to promote lifespan and healthspan in aging populations. To understand the mechanisms mediating many of the interventions discussed in this review, we also provide an overview of the gut microbiome’s relationships with the immune system, aging, and the brain. Importantly, we explore how inflammageing (low-grade chronic inflammation that often develops with age), systemic inflammation, and senescent cells may arise from and relate to the gut microbiome. Furthermore, we explore in detail the complex gut–brain axis and the evidence surrounding how gut dysbiosis may be implicated in several age-associated neurodegenerative diseases. We also examine current research on potential interventions for healthspan and lifespan as they relate to the changes taking place in the microbiome during aging; and we begin to explore how the reduction in senescent cells and senescence-associated secretory phenotype (SASP) interplay with the microbiome during the aging process and highlight avenues for further research in this area.

Aggression is a complex social behaviour that allows individuals to compete for access to limited resources (eg, mates, food and territories). Excessive or inappropriate aggression, however, has become problematic in modern societies, and current treatments are largely ineffective. Although previous work in mammals suggests that aggressive behaviour varies seasonally, seasonality is largely overlooked when developing clinical treatments for inappropriate aggression. Here, we investigated how the hormone melatonin regulates seasonal changes in neurosteroid levels and aggressive behaviour in Siberian hamsters, a rodent model of seasonal aggression. Specifically, we housed males in long‐day (LD) or short‐day (SD) photoperiods, administered timed s.c. melatonin injections (which mimic a SD‐like signal) or control injections, and measured aggression using a resident‐intruder paradigm after 9 weeks of treatment. Moreover, we quantified five steroid hormones in circulation and in brain regions associated with aggressive behaviour (lateral septum, anterior hypothalamus, medial amygdala and periaqueductal gray) using liquid chromatography‐tandem mass spectrometry. SD hamsters and LD hamsters administered timed melatonin injections (LD‐M) displayed increased aggression and exhibited region‐specific decreases in neural dehydroepiandrosterone, testosterone and oestradiol, but showed no changes in progesterone or cortisol. Male hamsters also showed distinct associations between neurosteroids and aggressive behaviour, in which neural progesterone and dehydroepiandrosterone were positively correlated with aggression in all treatment groups, whereas neural testosterone, oestradiol and cortisol were negatively correlated with aggression only in LD‐M and SD hamsters. Collectively, these results provide insight into a novel neuroendocrine mechanism of mammalian aggression, in which melatonin reduces neurosteroid levels and elevates aggressive behaviour.

Seasonally breeding animals undergo shifts in physiology and behavior in response to changes in photoperiod (day length). Interestingly, some species, such as Siberian hamsters (Phodopus sungorus), are more aggressive during the short-day photoperiods of the non-breeding season, despite gonadal regression. While our previous data suggest that Siberian hamsters employ a ‘seasonal switch’ from gonadal to adrenal regulation of aggression during short-day photoperiods, there is emerging evidence that the gut microbiome, an environment of symbiotic bacteria within the gastrointestinal tract, may also change seasonally and modulate social behaviors. The goal of this study was to compare seasonal shifts in the gut microbiome, circulating levels of adrenal dehydroepiandrosterone (DHEA) and aggression in male and female Siberian hamsters. Hamsters were housed in either long-day (LD) or short-day (SD) photoperiods for 9 weeks. Fecal samples were collected and behaviors were recorded following 3, 6 and 9 weeks of housing, and circulating DHEA was measured at week 9. SD females that were responsive to changes in photoperiod (SD-R), but not SD-R males, displayed increased aggression following 9 weeks of treatment. SD-R males and females also exhibited distinct changes in the relative abundance of gut bacterial phyla and families, yet showed no change in circulating DHEA. The relative abundance of some bacterial families (e.g. Anaeroplasmataceae in females) was associated with aggression in SD-R but not LD or SD non-responder (SD-NR) hamsters after 9 weeks of treatment. Collectively, this study provides insight into the complex role of the microbiome in regulating social behavior in seasonally breeding species.