AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic ...processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for ...conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.
Objectives
To characterize caregiver strain, depressive symptoms, and self‐efficacy for managing dementia‐related problems and the relationship between these and referring provider type.
Design
...Cross‐sectional observational cohort.
Setting
Urban academic medical center.
Participants
Caregivers of community‐dwelling adults with dementia referred to a dementia care management program.
Measurements
Caregivers were surveyed and completed the Patient Health Questionnaire (PHQ‐9) about themselves; the Modified Caregiver Strain Index; the Neuropsychiatric Inventory Questionnaire, which measures patient symptom severity and related caregiver distress; and a nine‐item caregiver self‐efficacy scale developed for the study.
Results
Of 307 patient–caregiver dyads surveyed over a 1‐year period, 32% of caregivers reported confidence in managing dementia‐related problems, 19% knew how to access community services to help provide care, and 28% agreed that the individual's provider helped them work through dementia care problems. Thirty‐eight percent reported high levels of caregiver strain, and 15% reported moderate to severe depressive symptoms. Caregivers of individuals referred by geriatricians more often reported having a healthcare professional to help work through dementia care problems than those referred by internists, family physicians, or other specialists, but self‐efficacy did not differ. Low caregiver self‐efficacy was associated with higher caregiver strain, more caregiver depressive symptoms, and caring for an individual with more‐severe behavioral symptoms.
Conclusion
Most caregivers perceived inadequate support from the individual's provider in managing dementia‐related problems, reported strain, and had low confidence in managing caregiving. New models of care are needed to address the complex care needs of individuals with dementia and their caregivers.
One of the major metabolic changes associated with cellular transformation is enhanced nutrient utilization, which supports tumor progression by fueling both energy production and providing ...biosynthetic intermediates for growth. The liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor that couples bioenergetics to cell-growth control through regulation of mammalian target of rapamycin (mTOR) activity; however, the influence of LKB1 on tumor metabolism is not well defined. Here, we show that loss of LKB1 induces a progrowth metabolic program in proliferating cells. Cells lacking LKB1 display increased glucose and glutamine uptake and utilization, which support both cellular ATP levels and increased macromolecular biosynthesis. This LKB1-dependent reprogramming of cell metabolism is dependent on the hypoxia-inducible factor-1α (HIF-1α), which accumulates under normoxia in LKB1-deficient cells and is antagonized by inhibition of mTOR complex I signaling. Silencing HIF-1α reverses the metabolic advantages conferred by reduced LKB1 signaling and impairs the growth and survival of LKB1-deficient tumor cells under low-nutrient conditions. Together, our data implicate the tumor suppressor LKB1 as a central regulator of tumor metabolism and growth control through the regulation of HIF-1α–dependent metabolic reprogramming.
Multimorbidity occurs in adults of all ages, but the number and complexity of comorbid conditions commonly increase with advancing age such that cardiovascular disease (CVD) in older adults typically ...occurs in a context of multimorbidity. Current clinical practice and research mainly target single disease-specific care that does not embrace the complexities imposed by concurrent conditions. In this paper, emerging concepts regarding CVD in combination with multimorbidity are reviewed, including recommendations for incorporating multimorbidity into clinical decision making, critical knowledge gaps, and research priorities to optimize care of complex older patients.
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Geriatric training is designed to prepare physicians to meet the complex needs of older adults, including persons with dementia at the end-of-life (EOL) stage. We sought to compare patterns of EOL ...care delivered to persons with dementia between physicians with versus without geriatric training.
We conducted a cross-sectional study of a 20% random sample of fee-for-service Medicare beneficiaries with dementia who died in 2016-2018 (n = 99,631). We attributed beneficiaries to a physician who had the largest number of primary care visits during the last 6 months of life and determined whether the physician was trained in geriatrics. Our outcome measures included: (i) advance care planning (ACP) and palliative care (e.g., ACP, hospice enrollment in the last 90 days of life), and (ii) high-intensity EOL care (e.g., emergency department visits or hospital admissions in the last 30 days of life).
Beneficiaries with dementia under the care of physicians with geriatric training had a higher proportion of ACP (adjusted proportion, 15.8% vs. 13.0%; p < 0.001 after accounting for multiple comparisons), palliative care counseling (22.4% vs. 20.9%; p = 0.01), and hospice enrollment (63.7% vs. 60.6%; p < 0.001). Geriatric training was also associated with a lower proportion of emergency department visits (55.1% vs. 59.1%; p < 0.001), hospital admissions (48.8% vs. 52.3%; p < 0.001), ICU admissions (24.9% vs. 27.4%; p < 0.001), use of mechanical ventilation (11.2% vs. 13.0%; p < 0.001), and use of cardiopulmonary resuscitation (2.1% vs. 2.4%; p = 0.03) in the last 30 days of life. There was no evidence that the placement of feeding tubes differed between the two groups.
Physicians' geriatric training was associated with the receipt of more ACP and palliative care and less intensive EOL care among persons with dementia. Provision of geriatric training for physicians may have the potential to improve the quality of EOL care delivered to persons with dementia.
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