Biology subjects

Calubag, M. F.

Publications and source records attributed to Calubag, M. F..

4 recordsLinked to original sources

bioRxiv2023

Restricting dietary protein or dietary isoleucine improves metabolic health in aged mice

In defiance of the paradigm that calories from all sources are equivalent, we and others have shown that dietary protein is a dominant regulator of healthy aging. The restriction of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan when initiated in young or adult mice. However, many interventions are less efficacious or even deleterious when initiated in aged animals. Here, we investigate the physiological, metabolic, and molecular consequences of consuming a diet with a 67% reduction of all amino acids (Low AA), or of isoleucine alone (Low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. We find that both diet regimens effectively reduce adiposity and improve glucose tolerance, which were benefits that were not mediated by reduced calorie intake. Both diets improve specific aspects of frailty, slow multiple molecular indicators of aging rate, and rejuvenate the aging heart and liver at the molecular level. These results demonstrate that Low AA and Low Ile diets can drive youthful physiological and molecular signatures, and support the possibility that these dietary interventions could help to promote healthy aging in older adults.

physiology↗

bioRxiv2022

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

physiology↗

bioRxiv2022

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 Fgf21-/-and wild-type control mice either ad libitum (AL) diet or a 30% CR diet for 15 weeks. Here, we find that FGF21 is largely dispensable for CR-induced improvements in body composition and energy balance, but that lack of Fgf21 blunts CR-induced changes aspects of glucose regulation and insulin sensitivity in females. Surprisingly, despite not affecting CR-induced changes in energy expenditure, loss of Fgf21 significantly blunts CR-induced beiging of white adipose tissue in male but not female mice. Our results shed new light on the molecular mechanisms involved in the beneficial effects of a CR diet, clarify that FGF21 is largely dispensable for the metabolic effects of a CR diet, and highlight a sex-dependent role for FGF21 in the molecular adaptation of white adipose tissue to CR.

physiology↗

bioRxiv2021

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. However, due to a lack of suitable isozyme-specific tools, the role of the novel subfamily of PKC isozymes is largely unknown. Here, through the development of FLIM-FRET activity sensors, we investigate novel PKC isozymes in synaptic plasticity in mouse CA1 pyramidal neurons. We find that PKC{delta} is activated downstream of TrkB and that the spatiotemporal nature of its activation depends on the plasticity stimulation. In response to single spine plasticity, PKC{delta} is activated primarily in the stimulated spine and is required for local expression of plasticity. However, in response to multi-spine stimulation, a long-lasting and spreading activation of PKC{delta} scales with the number of spines stimulated and, by regulating CREB activity, couples spine plasticity to transcription in the nucleus. Thus, PKC{delta} plays a dual functional role in facilitating synaptic plasticity.

neuroscience↗