Exercise habits and ageing health : exploring the associations of FGF21 and lung microbiome in glycaemic regulation, bone health, arterial stiffness and respiratory health

• Main Author: Lee, Shuen Yee
• Other Authors: Fabian Lim
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Science::Medicine
• Online Access: https://hdl.handle.net/10356/136835
• Institution: Nanyang Technological University

Advancing age causes progressive decline in physiological functions and increases the risk of diseases and death. Age is an independent predictor of non-communicable chronic diseases such as bone fragility and respiratory and metabolic diseases, including cardiovascular disease and type 2 diabetes mellitus (T2DM). Besides age, there is good consensus among researchers and professional institutions that physical inactivity is another important factor that increases the risk of age-associated chronic diseases. Contralaterally, there is much research evidence supporting the effects of exercise in preventing and mitigating the effects of age-associated chronic conditions. Age-associated chronic disease accounted for ~71% of deaths globally and with the projected two-fold increase in elderly population worldwide by 2050, age-associated chronic disease-related mortality rate is also projected to increase exponentially in the next three decades. The increasing burden of age-associated chronic disease globally implies the sub-optimal effectiveness of existing healthcare models and therapeutics in treating and controlling these conditions at the population level. While it is not possible to reverse the growth of older population, more can be done through biomedical research to understand better the mechanisms underlying the favourable effects of exercise on ageing health, which may lead to potential therapeutic targets for preventing or decelerating the risk of age-associated chronic diseases. There is growing interest in the therapeutic role of fibroblast growth factor 21 (FGF21) and the microbiome in age-associated conditions. The primary aim of this thesis was to investigate the associations of FGF21 with the effects of age and habitual exercise on glucose regulation, bone mass, oxidative stress and arterial stiffness. The thesis also explored the effects of age on lung microbiome and the associations with arterial stiffness and lung function. The aims of the thesis were investigated through a review of relevant research evidence and four studies. The review of the literature discussed research evidence related to age-associated decline in important physiological functions, including the loss in bone mass, decline in glucoregulatory function and increase in arterial stiffness. The effects of exercise on glucose regulation and arterial stiffness was also discussed in the review. The potential mechanisms driving the age-and exercise-associated effects on glucose regulation, arterial stiffness and bone loss were also examined. The review discussed the potential role of the microbiome, especially in the lungs, and its impact on ageing health. The effects of ageing and exercise on FGF21, and the glucoregulatory and anti-oxidative function of FGF21, and its impact on bone loss was also reviewed in this chapter. The downstream mechanistic pathways of FGF21, including adiponectin and insulin-like growth factor binding protein 1 (IGFBP1) were also discussed in the review. Although the evidence supports that FGF21 and the lung microbiome play important roles in metabolic, bone and respiratory health, none of the studies have investigated whether FGF21 and the lung microbiome were associated with age- and exercise-related changes in physiology, especially in healthy people. The aim of study 1 was to investigate the association between FGF21 and glucose regulation, under the influence of exercise habits and ageing in healthy individuals. The hypothesis that glucose regulation with habitual exercise and ageing are associated with FGF21 is supported. In a cross-sectional study design, the concentrations of blood glucose and plasma FGF21, insulin and adiponectin during an oral glucose challenge were compared between 80 healthy individuals across young active (YA), young sedentary (YS), older active (OA) and older sedentary (OS) groups. FGF21 and insulin concentrations during the oral glucose challenge were lower in habitually active than sedentary individuals, independent of age. Ageing was associated with an increase in glucose and FGF21 concentrations during the OGTT, independent of exercise habits. Adiponectin concentrations were not affected by age or habitual exercise. The results imply that FGF21 may modulate the associations between ageing and habitual exercise on glucose regulation, independent of adiponectin. The aim of study 2 was to investigate the FGF21-associated pathways in arterial stiffness, under the influence of ageing and habitual exercise in healthy individuals, in the same cross-sectional groups and participants as Study 1. A secondary aim of this study was to investigate the associations of FGF21 with oxidative stress and arterial stiffness. The plasma concentrations of FGF21, adiponectin and oxidized low-density lipoprotein (an oxidative stress marker), and arterial stiffness measures were compared between 80 healthy individuals in YA, YS, OA and OS groups. Oxidative stress and arterial stiffness were higher in older than younger adults, despite no difference in FGF21 and adiponectin concentrations between younger and older groups, independent of exercise habits. Oxidative stress and arterial stiffness were also not different between habitually active and sedentary individuals, but FGF21 was associated positively with arterial stiffness in the sedentary group only, independent of age. In contrary to my hypotheses, these results imply that ageing, but not self-reported exercise habits, likely increases oxidative stress and arterial stiffness. The hypothesis that FGF21-associated pathways are related to oxidative stress and arterial stiffness is defeated. Study 3 investigated the associations of FGF21 in bone turnover and decline in bone mineral density (BMD) during ageing, between 20 pairs of healthy younger and older family members. The hypothesis that FGF21 concentration is positively associated with age-associated bone loss is supported, but the involvement of IGFBP1 is not supported. Serum concentrations of FGF21, IGFBP1, receptor activator of nuclear factor kappa-B ligand (RANKL), bone formation marker bone-specific alkaline phosphatase (BAP) and bone resorption marker tartrate-resistant acid phosphatase 5b (TRAP5b) and BMD were measured in younger and older family pairs. Compared with younger adults, older adults had higher FGF21 concentration, no change in IGFBP1 concentration, lower RANKL concentration, and higher concentrations of TRAP5b and BAP and lower BMD. These results imply that FGF21 is related to age-associated increase in bone remodelling and decline in BMD. Contrary to current evidence, IGFBP1 may not be a downstream effector of FGF21 and IGFBP1 is unlikely involved in RANKL-associated osteoclast differentiation in healthy humans. Study 4 explored the age-associated changes in lung microbiome and their links with arterial stiffness and lung function in the same 24 pairs of healthy younger and older family members. Bacterial microbiome composition was determined from sputum samples and arterial stiffness and lung function measures were compared between younger and older family pairs. Ageing was associated with an increase in relative abundance of Firmicutes and a decrease relative abundance of Proteobacteria. Different microbes in the lungs were independently associated with lung function and arterial stiffness, in an age-dependent manner. The hypothesis that age-associated changes in lung microbiome composition is related with changes in the lung function and arterial stiffness during ageing is supported. The results from these studies support that in healthy individuals, FGF21-associated pathways are related to age- and habitual exercise-associated effects on glucose regulation, arterial stiffness and bone mass. The data also suggest that the downstream pathway of FGF21 is not associated with adiponectin and IGFBP1. The exploratory study on the airway microbiome support that the lung microbiome is plausibly associated with age-related decline in physiological function. These results imply that FGF21 and the lung microbiome are important factors related to the normative age- and exercise-associated physiological changes in healthy individuals, which support their possibility as effective targets to prevent or decelerate age-associated disease onset. Future studies should focus on elucidating the downstream mechanisms that drive the effects of FGF21 and lung microbiome on ageing health.