Title: Central-peripheral Homeostatic (dys)function in Metabolic Aging Modelled in Amyotrophic Lateral Sclerosis Transgenic Mice

Aging is related to several changes in metabolic rates and metabolism control unfolding at different level, from cell-autonomous dysfunctions to altered homeostatic manteinance of energy balance. The formers have been consistely linked to the dysfunction of mitochondria; on the other hand, the latter seems to be related to altered senstivity or function of hypothalamic nuclei. In normal aging, mitochondrial dysfunctions not only reduce the efficiency of metabolic conversion, but also influence transcriptional landscapes, apoptosis, inflammatory reactions of organs and tissues with high energy demands such as skeletal muscles, retina, inner hear and brain. On the other hand, hypothalamic control of bodily functions decreases over time, and the central disregulation adds to the burden of cellautonomous alterations by exausting functional reserve in adipose tissue, skeletal muscle and modifying the overall metabolic rate; notably, hypothalamic function is a strong modulator of lifespan itself, as shown by the prolonged survival of GHR-KO and IGF-I-KO mice. Therefore, the aging process unfolding at mitochondrial level can cause hypothalamic dysfunction, and in turn improper hypothalamic function may worsen underlying mitochondrial alterations. Thus, metabolic aging can be conceptualized as the progressively disfunctional interaction between central regulators and body-wide executors of turnover and energy balance. Neurodegenerative conditions offer unique entry points to understand the relative contributions of peripheral and central mechanisms in metabolic aging. In fact, in neurodegeneration-related models the neurometabolic aging can be studied in relative isolation from the aging process affecting other organs or systems and with molecularly defined entry points. Furthermore, genetically-defined models offer tractable systems in which hypothalamic or mitochondrial dysfunctions can be modelled independently, with high resolution both in terms of molecular events and the timeframe of their unfolding. To this respect, Amyotrophic Lateral Sclerosis (ALS) provides a compelling system of the study of metabolic aging: disfunction of metabolism is an early phenotype, it affects both nervous and non-nervous structures, and both mitochondrial and hypothalamic dysfunctions have been identified; nevertheless, alteration of the CNS is restricted to specific circuits and substructures that can be understood at cellular level. Therefore, ALS offers an ideal model to study how disturbances of central metabolic regulators and peripheral mitochondrial systems interact to amplify or compensate each other as a critical aspect of physiological aging and ultimately affect lifespan. Preliminary work. We have shown that ALS models display both peripheral (i.e., nonnervous) and central (hypothalamic) dysfunctions affecting organs and structures involved in neurometabolic aging. Transgenic mice expressing mutant forms of SOD1 targeting the mitochondrium display both ALS-like pathology and generalized energy deficit and hypermetabolism, recapitulating the impaired mitochondrial energy metabolism observed in patients. On the other hand, both ALS patients and mouse models display structural and functional alterations of hypothalamic structures. Interestingly, ALS patients who displayed increased blood lipid levels showed prolonged survival, implying a peripheral control lifespan in this disease. Likewise over-expression of uncoupling protein 1 in muscle is sufficient to cause generalized hypermetabolism and concomitant motor neuron degeneration. Furthermore we observed that dynein mutant mice, which mimic ALS-related axonal transport defects, showed compromised thermogenesis. In summary, we have shown that ALS models display both peripheral and central neurometabolic abnormalities similar to those observed in normal aging. However, the site of initiator factors (central or peripheral) and the dysfunctional retroaction loops which may amplify them have not been clarified.