Thursday · Oct 8
9:00 to 11:00

Stress, Inflammation and Aging: What`s new on this relationship?

Maria Jose Bellini

Centro de Investigaciones Biomédicas (CINBIO). Universidad de Vigo (España)

Chronic stress accelerates aging. A wide range of studies has shown that stress can speed-up the aging process and also that inflammation becomes a response to stress and aging. This symposium provides a summary of the state of research on stress and aging-related changes associated with factors such as inflammation and/or sex that may contribute to differential responses and susceptibility to damage and therapies. The following talks provide an integrated view on future direction in stress and aging research and interventions targeting inflammation.

Perinatal stress and brain inflammation

Yolanda Diz-Chaves

Centro de Investigaciones Biomédicas (CINBIO). Universidad de Vigo (España)

Stressing life experiences occurring during perinatal life may result in permanent alterations in the function of the nervous, immune and metabolic systems. Maternal stress increases the inflammatory response in the offspring, altering brain function by the modification of local inflammation, increasing the risk of depression, schizophrenia and autism. Mother restraint stress (MRS), increases IL1β mRNA levels in the hippocampus of both male and female pups. Also, TNFα mRNA levels and immunoreactivity in CA1 are increased in males. The total number and reactivity of Iba1-immunoreactive cells are augmented both in male and females, corresponding to a reactive status. Maternal perinatal food restriction (MPFR) in rats, increases the mRNA expression of proinflammatory mediators and the number of GFAP and Iba1-immunopositive cells in the dentate gyrus of males but not in females rats. Moreover, LPS administration induces a significant increase in proinflammatory indicators and Iba1-immunoreactive cells in the hippocampus of prenatally stressed pups. Perinatal stress-induced generates long-lasting modifications in the inflammatory status of the hippocampus both in mice and rats. Also, an evident sexual dimorphism in the case of MPFR is observed. Furthermore, MRS alters the immune response of the hippocampus to peripheral inflammation that results in enhanced activation of microglia and astrocytes in response to a proinflammatory insult.

Circadian prenatal programming of the stress axis

Mariana Astiz

Institute of Neurobiology, Center of Brain, Behavior and Metabolism, University of Lübeck, Germany

During pregnancy, maternal endocrine signals such as glucocorticoids (GCs) drive fetal development and program physiology. GCs are produced by the hypothalamic-pituitary-adrenal (HPA) axis every day at the beginning of the active phase and in response to stress. A disruption of maternal GC homeostasis, increases the offspring’s risk of developing psychiatric disorders later in life. We show that the time of GC administration, rather than the dose, is a predictor of behavioral phenotypes in mice. Offspring of mothers receiving GCs out-of-phase compared to their own circadian rhythm show elevated anxiety, impaired stress coping and stress axis regulation. On the other hand, if the maternal exposure takes place at the beginning of the active phase, the phenotype of the offspring is comparable to that of control mice. These differences suggest the involvement of the circadian clock “gating” the GC-induced programming effects. When we followed up the underlying mechanism, we found that the fetal clock, specifically the clock protein REVERBα, determines the sensitivity to GC treatment by controlling the daily availability of the GC receptor (GR) in the hypothalamus. Similarly, in a retrospective observational analysis in humans we found that children whose mothers received antenatal GCs out-of-phase compared to their own circadian rhythm tend to show altered stress-related behavior at the age of 5.


Maria Jose Bellini

1 Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP)- Facultad de Ciencias Médicas, Universidad Nacional de La Plata-CONICET-La Plata, Buenos Aires, Argentina

Our research focusses on the possible modulation of neural cells and brain outcomes during aging process employing IGF-1 gene therapy, a molecule known to be essential for synaptic plasticity and neuronal survival. In this work, we explored the effects of gene therapy in two experimental models of natural aging: aged mice (male and female) and senile female rat. First, we quantified frailty through a clinical assessment of aged mice, to explain the heterogeneity in clinical outcomes for older patients. We compared the 31-items Clinical Frailty Index and a set of behavioral tests in mice of 24 months before and after intramuscular IGF-1 gene therapy. We observed a clear effect of therapy in both sexes. Considering that sex is a factor that influences the incidence of all major complex diseases, our principal outcome is to use different frailty indexes calculations to identify sex differences and therapy efficiency in aging models. We also explore the effects of IGF-1 gene therapy on microglial cells in 28 months old female rats. We found that IGF-1 influences microglial number, phagocytic activity, and transcriptomic expression; suggesting that IGF-1 gene therapy could be an effective treatment to modulate microglial activation and to induce an anti-inflammatory microenvironment favorable to neuronal survival. Our work reinforces the beneficial effects of IGF-1 on aging and could be a useful tool to treat age-related neurodegenerative pathologies in a sex-specific manner.

Sex differences in brain mitochondria: Differential response and susceptibility to cellular damage?

George E. Barreto

Department of Biological Sciences, University of Limerick, Limerick, Ireland

Mitochondria respond differentially to brain damage, and these mechanisms may be important during acute inflammation and for repair during the post-injury period. At basal levels, the expression of cytokines and chemokines are different in men vs women’s brain, and so is the production of oxidative stress coupled with the mitochondrial membrane potential and the mitochondrial permeability transition pore. Interestingly, the activity/expression of some mitochondrial complexes of the electron transport chain are more expressed in women, and this raises the hypothesis that endogenous hormones may be playing a role in promoting said mitochondrial activity. By inducing early menopause in animals (ovariectomy and orchidectomy) and cells (siRNA aromatase) there is a shift in lipid metabolism and this is reflected on how mitochondria respond to metabolic damage. A large part of these effects may be related to the expression of neuroglobin, a cytosolic protein, but which, in the face of brain trauma, is transported to mitochondria where it interacts with Complex I and, mostly Complex III, and proteins such as cyc1, ETFDH/Q/ETFA and p32/c1qbp complexes, thus regulating apoptotic mechanisms, oxidative phosphorylation, mitochondrial immunometabolism, and these are all different depending on the sex. In this talk, we will discuss these mitochondrial mechanisms responsible for a response to metabolic damage, emphasizing how the female mitochondria respond differently compared to males.