Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of Trem2-mediated microglial activation.

Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder enlargement, as well as lipid dyshomeostasis.

The RAD51 S181P mutation shortens lifespan of female mice.

RAD51 is critical to the homologous recombination (HR) pathway that repairs DNA double strand breaks (DSBs) and protects replication forks (RFs). Previously, we showed that the S181P (SP) mutation in RAD51 causes defective RF maintenance but is proficient for DSB repair. Here we report that SP/SP female mice exhibit a shortened lifespan compared to +/+ females but not males.

Rapamycin Extends Life Span in Apc Colon Cancer FAP Model.

Background: We previously showed that lifelong rapamycin treatment of short-lived Apc mice, a model for familial adenomatous polyposis, resulted in a normal lifespan. Apc mice develop colon polyps with a low frequency but can be converted to a colon cancer model by dextran sodium sulfate (DSS) treatments (Apc-DSS model).

Materials And Methods: We asked, what effect would pretreatment of Apc mice with chronic rapamycin prior to DSS exposure have on survival and colonic neoplasia?

Results: Forty-two ppm enteric formulation of rapamycin diet exacerbated the temporary weight loss associated with DSS treatment in both sexes.

Acarbose improved survival for Apc mice.

Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice.

Sex-dependent lifespan extension of FAP mice by chronic mTOR inhibition.

Background: mice model familial adenomatous polyposis (FAP), a disease that causes numerous colon polyps leading to colorectal cancer. We previously showed that chronic treatment of females with the anti-aging drug, rapamycin, restored a normal lifespan through reduced polyposis and anemia prevention. Lifespan extension by chronic rapamycin in wildtype UM-HET3 mice is sex-dependent with females gaining the most benefit.

Adaptations to chronic rapamycin in mice.

Rapamycin inhibits mechanistic (or mammalian) target of rapamycin (mTOR) that promotes protein production in cells by facilitating ribosome biogenesis (RiBi) and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa) extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level.

p53 and rapamycin are additive.

Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing.

Deletion of BRCA2 exon 27 causes defects in response to both stalled and collapsed replication forks.

BRCA2 is a tumor suppressor that maintains genomic integrity through double strand break (DSB) repair and replication fork protection. The BRC motifs and an exon 27-encoded domain (Ex27) of BRCA2 interact with the recombinase RAD51 to, respectively, facilitate the formation and stability of a RAD51 filament on single strand DNA. The BRC-RAD51 associations enable DSB repair while the Ex27-RAD51 association protects the nascent replication strand from MRE11-mediated degradation.

Deletion of BRCA2 exon 27 causes defects in response to both stalled and collapsed replication forks.

BRCA2 is a tumor suppressor that maintains genomic integrity through double strand break (DSB) repair and replication fork protection. The BRC motifs and an exon 27-encoded domain (Ex27) of BRCA2 interact with the recombinase RAD51 to, respectively, facilitate the formation and stability of a RAD51 filament on single strand DNA. The BRC-RAD51 associations enable DSB repair while the Ex27-RAD51 association protects the nascent replication strand from MRE11-mediated degradation.

Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage.

Cancer prevention is a cost-effective alternative to treatment. In mice, the mTOR inhibitor rapamycin prevents distinct spontaneous, noninflammatory cancers, making it a candidate broad-spectrum cancer prevention agent. We now show that oral microencapsulated rapamycin (eRapa) prevents skin cancer in dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) carcinogen-induced, inflammation-driven carcinogenesis.

RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway.

Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes.

Divergent tissue and sex effects of rapamycin on the proteasome-chaperone network of old mice.

Rapamycin, an allosteric inhibitor of the mTOR kinase, increases longevity in mice in a sex-specific manner. In contrast to the widely accepted theory that a loss of proteasome activity is detrimental to both life- and healthspan, biochemical studies in vitro reveal that rapamycin inhibits 20S proteasome peptidase activity. We tested if this unexpected finding is also evident after chronic rapamycin treatment in vivo by measuring peptidase activities for both the 26S and 20S proteasome in liver, fat, and brain tissues of old, male and female mice fed encapsulated chow containing 2.

eRapa restores a normal life span in a FAP mouse model.

Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. Apc(Min/+) mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve Apc(Min/+) mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span.

SULT2B1b sulfotransferase: induction by vitamin D receptor and reduced expression in prostate cancer.

An elevated tumor tissue androgen level, which reactivates androgen receptor in recurrent prostate cancer, arises from the intratumor synthesis of 5α-dihydrotestosterone through use of the precursor steroid dehydroepiandrosterone (DHEA) and is fueled by the steroidogenic enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD1), aldoketoreductase (AKR1C3), and steroid 5-alpha reductase, type 1 (SRD5A1) present in cancer tissue. Sulfotransferase 2B1b (SULT2B1b) (in short, SULT2B) is a prostate-expressed hydroxysteroid SULT that converts cholesterol, oxysterols, and DHEA to 3β-sulfates. DHEA metabolism involving sulfonation by SULT2B can potentially interfere with intraprostate androgen synthesis due to reduction of free DHEA pool and, thus, conversion of DHEA to androstenedione.

Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors.

Chronic treatment of mice with an enterically released formulation of rapamycin (eRapa) extends median and maximum life span, partly by attenuating cancer. The mechanistic basis of this response is not known. To gain a better understanding of thesein vivo effects, we used a defined preclinical model of neuroendocrine cancer, Rb1+/- mice.