Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF

Circadian clock: linking epigenetics to aging

Circadian rhythms are generated by an intrinsic cellular mechanism that controls a large array of physiological and metabolic processes. There is erosion in the robustness of circadian rhythms during aging, and disruption of the clock by genetic ablation of specific genes is associated with aging-related features. Importantly, environmental conditions are thought to modulate the aging process. For example, caloric restriction is a very strong environmental effector capable of delaying aging. Intracellular pathways implicating nutrient sensors, such as SIRTs and mTOR complexes, impinge on cellular and epigenetic mechanisms that control the aging process. Strikingly, accumulating evidences indicate that these pathways are involved in both the modulation of the aging process and the control of the clock. Hence, innovative therapeutic strategies focused at controlling the circadian clock and the nutrient sensing pathways might beneficially influence the negative effects of aging

SIRT1 relays nutritional inputs to the circadian clock through the Sf1 neurons of the ventromedial hypothalamus

Circadian rhythms govern homeostasis and organism physiology. Nutritional cues act as time-givers, contributing to the synchronization between central and peripheral clocks. Neuronal food-synchronized clocks are thought to reside in hypothalamic nuclei such as the ventromedial hypothalamus (VMH) and the dorsomedial hypothalamus (DMH), or extra hypothalamic brain areas such as nucleus accumbens (NA). Interestingly, the metabolic sensor NAD(+)-dependent deacetylase SIRT1 is highly expressed in the VMH and was shown to contribute to both control of energy-balance and clock function. We used mice with targeted ablation of Sirt1 in the Sf1 neurons of the VMH to gain insight on the role played by this deacetylase in the modulation of the central clock by nutritional inputs. By studying circadian behavior and circadian gene expression we reveal that SIRT1 operates as a metabolic sensor connecting food intake to circadian behavior. Indeed, under food restriction and absence of light, SIRT1 in the VMH contributes to activity behavior and circadian gene expression in the SCN. Thus, under specific physiological conditions, SIRT1 contributes to the modulation of the circadian clock by nutrients

Spatial dynamics of SIRT1 and the subnuclear distribution of NADH species

Sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase that functions as metabolic sensor of cellular energy and modulates biochemical pathways in the adaptation to changes in the environment. SIRT1 substrates include histones and proteins related to enhancement of mitochondrial function as well as antioxidant protection. Fluctuations in intracellular NAD+ levels regulate SIRT1 activity, but how SIRT1 enzymatic activity impacts on NAD+ levels and its intracellular distribution remains unclear. Here, we show that SIRT1 determines the nuclear organization of protein-bound NADH. Using multiphoton microscopy in live cells, we show that free and bound NADH are compartmentalized inside of the nucleus, and its subnuclear distribution depends on SIRT1. Importantly, SIRT6, a chromatin-bound deacetylase of the same class, does not influence NADH nuclear localization. In addition, using fluorescence fluctuation spectroscopy in single living cells, we reveal that NAD+ metabolism in the nucleus is linked to subnuclear dynamics of active SIRT1. These results reveal a connection between NAD+ metabolism, NADH distribution, and SIRT1 activity in the nucleus of live cells and pave the way to decipher links between nuclear organization and metabolism

Spatial dynamics of SIRT1 and the subnuclear distribution of NADH species

Sirtuin 1 (SIRT1) is an NAD(+)-dependent deacetylase that functions as metabolic sensor of cellular energy and modulates biochemical pathways in the adaptation to changes in the environment. SIRT1 substrates include histones and proteins related to enhancement of mitochondrial function as well as antioxidant protection. Fluctuations in intracellular NAD(+) levels regulate SIRT1 activity, but how SIRT1 enzymatic activity impacts on NAD(+) levels and its intracellular distribution remains unclear. Here, we show that SIRT1 determines the nuclear organization of protein-bound NADH. Using multiphoton microscopy in live cells, we show that free and bound NADH are compartmentalized inside of the nucleus, and its subnuclear distribution depends on SIRT1. Importantly, SIRT6, a chromatin-bound deacetylase of the same class, does not influence NADH nuclear localization. In addition, using fluorescence fluctuation spectroscopy in single living cells, we reveal that NAD(+) metabolism in the nucleus is linked to subnuclear dynamics of active SIRT1. These results reveal a connection between NAD(+) metabolism, NADH distribution, and SIRT1 activity in the nucleus of live cells and pave the way to decipher links between nuclear organization and metabolism

The Circadian Clock in the Ventromedial Hypothalamus Controls Cyclic Energy Expenditure

Organismal homeostasis relies on coherent interactions among tissues, specifically between brain-driven functions and peripheral metabolic organs. Hypothalamic circuits compute metabolic information to optimize energetic resources, but the role of the circadian clock in these pathways remains unclear. We have generated mice with targeted ablation of the core-clock gene Bmal1 within Sf1-neurons of the ventromedial hypothalamus (VMH). While this mutation does not affect the central clock in the suprachiasmatic nucleus (SCN), the VMH clock controls cyclic thermogenesis in brown adipose tissue (BAT), a tissue that governs energy balance by dissipating chemical energy as heat. VMH-driven control is exerted through increased adrenergic signaling within the sympathetic nervous system, without affecting the BAT’s endogenous clock. Moreover, we show that the VMH circadian clock computes light and feeding inputs to modulate basal energy expenditure. Thus, we reveal a previously unsuspected circuit where an SCN-independent, hypothalamic circadian clock controls BAT function, energy expenditure and thermogenesis

Rapid-acting antidepressants and the circadian clock.

A growing number of epidemiological and experimental studies has established that circadian disruption is strongly associated with psychiatric disorders, including major depressive disorder (MDD). This association is becoming increasingly relevant considering that modern lifestyles, social zeitgebers (time cues) and genetic variants contribute to disrupting circadian rhythms that may lead to psychiatric disorders. Circadian abnormalities associated with MDD include dysregulated rhythms of sleep, temperature, hormonal secretions, and mood which are modulated by the molecular clock. Rapid-acting antidepressants such as subanesthetic ketamine and sleep deprivation therapy can improve symptoms within 24 h in a subset of depressed patients, in striking contrast to conventional treatments, which generally require weeks for a full clinical response. Importantly, animal data show that sleep deprivation and ketamine have overlapping effects on clock gene expression. Furthermore, emerging data implicate the circadian system as a critical component involved in rapid antidepressant responses via several intracellular signaling pathways such as GSK3β, mTOR, MAPK, and NOTCH to initiate synaptic plasticity. Future research on the relationship between depression and the circadian clock may contribute to the development of novel therapeutic strategies for depression-like symptoms. In this review we summarize recent evidence describing: (1) how the circadian clock is implicated in depression, (2) how clock genes may contribute to fast-acting antidepressants, and (3) the mechanistic links between the clock genes driving circadian rhythms and neuroplasticity

Hypothalamic circuits and aging: keeping the circadian clock updated

Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions