Restriction of individual branched-chain amino acids has distinct effects on the development and progression of Alzheimer's disease in 3xTg mice.

Dietary protein is a critical regulator of metabolic health and aging in diverse species. Recent discoveries have determined that many benefits of a low protein diet are the result of reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Intriguingly, each BCAA has distinct physiological and molecular effects, with restriction of isoleucine alone being sufficient to improve metabolic health and extend the lifespan of mice.

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.

Caloric restriction slows or prevents Alzheimer's disease in animal models. Calorie restriction is typically implemented in rodents through feeding once per day; as the animals quickly consume their food, they are subject to a prolonged self-imposed fasting period between meals. Here, we examine the distinct contributions of fasting and reduced calories to the beneficial effects of calorie restriction on Alzheimer's disease by placing male and female 3xTg and non-transgenic control mice on a series of diet regimens enabling us to dissect the effects of calories and fasting.

Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice.

Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.

Caloric restriction (CR) robustly extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketones, we decided to investigate the role of ketogenesis in CR using mice with whole-body ablation of , the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB).

Tissue-specific effects of dietary protein on cellular senescence are mediated by branched-chain amino acids.

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice.

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TC), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TC). We demonstrated that E-TC repurposes molecules traditionally associated with E-TC to regulate mitochondrial DNA expression in areas closely linked to synaptic activation.

Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging.

Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer's disease.

Caloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimer's disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.

Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice.

A nutrigeroscience approach: Dietary macronutrients and cellular senescence.

Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.

Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice.

Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD.

Protein restriction slows the development and progression of Alzheimer's disease in mice.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD.

Dual Regulation of Spine-Specific and Synapse-to-Nucleus Signaling by PKCδ during Plasticity.

The activity-dependent plasticity of synapses is believed to be the cellular basis of learning. These synaptic changes are mediated through the coordination of local biochemical reactions in synapses and changes in gene transcription in the nucleus to modulate neuronal circuits and behavior. The protein kinase C (PKC) family of isozymes has long been established as critical for synaptic plasticity.

DREADD-inactivation of dorsal CA1 pyramidal neurons in mice impairs retrieval of object and spatial memories.

The hippocampus, a medial temporal lobe brain region, is critical for the consolidation of information from short-term memory into long-term episodic memory and for spatial memory that enables navigation. Hippocampal damage in humans has been linked to amnesia and memory loss, characteristic of Alzheimer's disease and other dementias. Numerous studies indicate that the rodent hippocampus contributes significantly to long-term memory for spatial and nonspatial information.

FGF21 has a sex-specific role in calorie-restriction-induced beiging of white adipose tissue in mice.

Calorie restriction (CR) promotes healthspan and extends the lifespan of diverse organisms, including mice, and there is intense interest in understanding the molecular mechanisms by which CR functions. Some studies have demonstrated that CR induces fibroblast growth factor 21 (FGF21), a hormone that regulates energy balance and that when overexpressed, promotes metabolic health and longevity in mice, but the role of FGF21 in the response to CR has not been fully investigated. We directly examined the role of FGF21 in the physiological and metabolic response to a CR diet by feeding and wild-type control mice either (AL) diet or a 30% CR diet for 15 weeks.

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice.

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence-associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1-XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome.