Adipose tissue plays a central role in metabolic control by ensuring lipid and energy homeostasis and regulating important aspects of inflammation and immune function. Thus, maintaining a healthy lipid balance (lipostasis) is crucial. Disturbance of lipostasis leads to impaired adipose tissue function, a hallmark of obesity, and increases with age, raising the risk of metabolic disease. In the MetAGE project, we examine the role of lipostasis in the aging-associated decline of metabolic control and explore how nutritional interventions can be used to regain lipostasis control.

Proteostasis, the balance of protein synthesis, folding, spatial sequestration, and degradation, plays a crucial role in orchestrating the adaptation of the cellular proteome in response to metabolic stress. Its dysregulation is a characteristic of aging and promotes protein stress as well as accumulation of damaged and aggregated proteins, resulting in organellar and cellular dysfunction. In the MetAGE project, we investigate the mechanistic relationship between loss of proteostasis flexibility, metabolic control, and aging as well as the possibility to restore proteostasis control via different interventions.

Polyamines are highly implicated in aging. Depletion of polyamines accelerates aging, while the ad-ministration of the endogenous polyamine spermidine prolongs the health span and life span of model organisms. Polyamine metabolism is disturbed upon aging and age-associated disease, but has also been postulated to contribute to metabolic control. In the MetAGE project, we investigate how polyamines affect both proteostasis and lipostasis in the context of aging and its interventions.

Mitochondria play multiple crucial roles, for instance, in cellular energy production, calcium homeostasis, inter-organellar signaling and cell death regulation. Impaired mitochondrial function is a feature and driver of aging, having a profound impact on age-associated cellular and systemic metabolic rewiring. In the MetAGE project, we investigate the relationship between mitochondrial bioenergetics, mitochondria-specific autophagic degradation (mitophagy), and metabolic flexibility in aging as well as pharmacological possibilities to counteract the corresponding age-related functional decline.

The brain processes and integrates endocrine and nutritional information from the whole body and participates in a complex interorgan communication process to control nutrient partitioning and fat mass. At the same time, peripheral endocrine and nutritional signals are able to affect brain function, and metabolic diseases are linked to neuropsychiatric disorders, including major depression. In the MetAGE project, we are interested in deciphering the role of the brain in maintaining body weight and the metabolic flexibility of an organism during aging.

The immune system recognizes and responds to foreign objects, pathogens, and cancer cells. Upon aging, chronic, low-grade inflammation (inflammaging) and the gradual deterioration of the immune system (immunosenescence) result in decreased effectiveness in fighting infections and increased susceptibility to age-related diseases. In the MetAGE project, we investigate how nutritional and pharmacological approaches can counteract the age-associated decline of the immune system, inflammaging, susceptibility of infection, and how they modulate immune cell differentiation and function in various tissues.

Biological and psychosociocultural factors are important determinants of health and life span. Sexual dimorphism affects several aspects of disease - from mechanism, development, and progression to its prevalence, prognosis, and response to therapy. Therefore, in the MetAGE project, we study the influence of sex and sex hormones on metabolic health and aging as well as in response to aging interventions in both preclinical and clinical research. Our human trials are designed to inspect different phases of the aging life cycle, comparing pre- and postmenopausal women, groups of men at comparable age and specific vulnerable groups of women and men at high cardiometabolic risk. We also consider how gender-specific, age-related changes determine the patients' perception of disease.