Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice.

The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP3) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered "aging rate indicators" in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics.

Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice.

Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug.

Transient early life growth hormone exposure permanently alters brain, muscle, liver, macrophage, and adipocyte status in long-lived Ames dwarf mice.

The exceptional longevity of Ames dwarf (DF) mice can be abrogated by a brief course of growth hormone (GH) injections started at 2 weeks of age. This transient GH exposure also prevents the increase in cellular stress resistance and decline in hypothalamic inflammation characteristic of DF mice. Here, we show that transient early-life GH treatment leads to permanent alteration of pertinent changes in adipocytes, fat-associated macrophages, liver, muscle, and brain that are seen in DF mice. Ames DF mice, like Snell dwarf and GHRKO mice, show elevation of glycosylphosphatidylinositol specific phospholipase D1 in liver, neurogenesis in brain as indicated by BDNF and DCX proteins, muscle production of fibronectin type III domain-containing protein 5 (a precursor of irisin), uncoupling protein 1 as an index of thermogenic capacity in brown and white fat, and increase in fat-associated anti-inflammatory macrophages. In each case, transient exposure to GH early in life reverts the DF mice to the levels of each protein seen in littermate control animals, in animals evaluated at 15-18 months of age. Thus, many of the traits seen in long-lived mutant mice, pertinent to age-related changes in inflammation, neurogenesis, and metabolic control, are permanently set by early-life GH levels.

Concentrating hospital-wide deaths in a palliative care unit: the effect on place of death and system-wide mortality.

INTRODUCTION: We studied the impact of an 11-bed inpatient palliative care unit (PCU) on site of death and observed mortality in the health system, oncology, and palliative care units. Observers were concerned that an active PCU would attract dying patients and worsen comparative mortality rates for Medicare and U.S. News & World Report comparisons. METHODS: We reviewed 10 years of experience with all patients who died in the hospital before and after we opened our PCU in 2000. RESULTS: The PCU concentrated dying patients on the PCU but total deaths did not change over 10 years and remained approximately 3% of admissions. Within 2 years, one quarter of all health system decedents died on the PCU. The proportion who died on the oncology floor and general units declined, but the number of intensive care unit deaths did not change. CONCLUSIONS: An inpatient PCU did not increase the hospital-wide death rate. The PCU did change the site of death to a more appropriate venue for one quarter of patients.

A high-volume specialist palliative care unit and team may reduce in-hospital end-of-life care costs.

BACKGROUND: Current end-of-life hospital care can be of poor quality and high cost. High volume and/or specialist care, and standardized care with clinical practice guidelines, has improved outcomes and costs in other areas of cancer care. METHODS: The objective of this study was to measure the impact of the palliative care unit (PCU) on the cost of care. The PCU is a dedicated 11-bed inpatient (PCU) staffed by a high-volume specialist team using standardized care. We compared daily charges and costs of the days prior to PCU transfer to the stay in the PCU, for patients who died in the first 6 months after the PCU opened May 2000. We performed a case-control study by matching 38 PCU patients by diagnosis and age to contemporary patients who died outside the PCU cared for by other medical or surgical teams, to adjust for potential differences in the patients or goals of care. RESULTS: The unit admitted 237 patients from May to December 2000. Fifty-two percent had cancer followed by vascular events, immunodeficiency, or organ failure. For the 123 patients with both non-PCU and PCU days, daily charges and costs were reduced by 66% overall and 74% in "other" (medications, diagnostics, etc.) after transfer to the PCU (p < 0.0001 for all). Comparing the 38 contemporary control patients who died outside the PCU to similar patients who died in the PCU, daily charges were 59% lower (US dollars 5304 +/- 5850 to US dollars 2172 +/- 2250, p = 0.005), direct costs 56% lower (US dollars 1441 +/- 1438 to US dollars 632 +/- 690, p = 0.004), and total costs 57% lower (US dollars 2538 +/- 2918 to US dollars 1095 +/- 1153, p = 0.009). CONCLUSIONS: Appropriate standardized care of medically complex terminally ill patients in a high-volume, specialized unit may significantly lower cost. These results should be confirmed in a randomized study but such studies are difficult to perform.