Publications by authors named "Richard A Miller"

222 Publications

A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.

Elife 2021 May 14;10. Epub 2021 May 14.

Max Planck Institute for Biology of Ageing, Cologne, Germany.

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.
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http://dx.doi.org/10.7554/eLife.62233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186904PMC
May 2021

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex.

Aging Cell 2021 05 31;20(5):e13328. Epub 2021 Mar 31.

Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.

In genetically heterogeneous mice produced by the CByB6F1 x C3D2F1 cross, the "non-feminizing" estrogen, 17-α-estradiol (17aE2), extended median male lifespan by 19% (p < 0.0001, log-rank test) and 11% (p = 0.007) when fed at 14.4 ppm starting at 16 and 20 months, respectively. 90th percentile lifespans were extended 7% (p = 0.004, Wang-Allison test) and 5% (p = 0.17). Body weights were reduced about 20% after starting the 17aE2 diets. Four other interventions were tested in males and females: nicotinamide riboside, candesartan cilexetil, geranylgeranylacetone, and MIF098. Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested. The 17aE2 results confirm and extend our original reports, with very similar results when started at 16 months compared with mice started at 10 months of age in a prior study. The consistently large lifespan benefit in males, even when treatment is started late in life, may provide information on sex-specific aspects of aging.
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http://dx.doi.org/10.1111/acel.13328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135004PMC
May 2021

CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

Lukuru Wildlife Research Foundation, Tshuapa-Lomami-Lualaba Project, BP 2012, Kinshasa, Democratic Republic of the Congo.

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of -linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons ( spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.
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http://dx.doi.org/10.1073/pnas.2025914118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020793PMC
March 2021

Cap-independent translation: A shared mechanism for lifespan extension by rapamycin, acarbose, and 17α-estradiol.

Aging Cell 2021 05 20;20(5):e13345. Epub 2021 Mar 20.

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

We hypothesized that rapamycin (Rapa), acarbose (ACA), which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA-KO, and Ghr-/- mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT). Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.
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http://dx.doi.org/10.1111/acel.13345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135077PMC
May 2021

Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects.

Aging Cell 2020 11 4;19(11):e13269. Epub 2020 Nov 4.

The Jackson Laboratory, Bar Harbor, ME, USA.

To see if variations in timing of rapamycin (Rapa), administered to middle aged mice starting at 20 months, would lead to different survival outcomes, we compared three dosing regimens. Initiation of Rapa at 42 ppm increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. Interpretation of these results is made more complicated by unanticipated variation in patterns of weight gain, prior to the initiation of the Rapa treatment, presumably due to the use of drug-free food from two different suppliers. The experimental design included tests of four other drugs, minocycline, β-guanidinopropionic acid, MitoQ, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), but none of these led to a change in survival in either sex.
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http://dx.doi.org/10.1111/acel.13269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681050PMC
November 2020

signatureSearch: environment for gene expression signature searching and functional interpretation.

Nucleic Acids Res 2020 12;48(21):e124

Institute for Integrative Genome Biology, 1207F Genomics Building, University of California, Riverside, CA 92521, USA.

signatureSearch is an R/Bioconductor package that integrates a suite of existing and novel algorithms into an analysis environment for gene expression signature (GES) searching combined with functional enrichment analysis (FEA) and visualization methods to facilitate the interpretation of the search results. In a typical GES search (GESS), a query GES is searched against a database of GESs obtained from large numbers of measurements, such as different genetic backgrounds, disease states and drug perturbations. Database matches sharing correlated signatures with the query indicate related cellular responses frequently governed by connected mechanisms, such as drugs mimicking the expression responses of a disease. To identify which processes are predominantly modulated in the GESS results, we developed specialized FEA methods combined with drug-target network visualization tools. The provided analysis tools are useful for studying the effects of genetic, chemical and environmental perturbations on biological systems, as well as searching single cell GES databases to identify novel network connections or cell types. The signatureSearch software is unique in that it provides access to an integrated environment for GESS/FEA routines that includes several novel search and enrichment methods, efficient data structures, and access to pre-built GES databases, and allowing users to work with custom databases.
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http://dx.doi.org/10.1093/nar/gkaa878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708038PMC
December 2020

Inhibition of class I PI3K enhances chaperone-mediated autophagy.

J Cell Biol 2020 12;219(12)

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.

Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.
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http://dx.doi.org/10.1083/jcb.202001031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557678PMC
December 2020

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.

Sci Adv 2020 Oct 2;6(40). Epub 2020 Oct 2.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in , although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.
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http://dx.doi.org/10.1126/sciadv.aaz7628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852388PMC
October 2020

Targeting the A2AR in cancer; early lessons from the clinic.

Curr Opin Pharmacol 2020 08 29;53:126-133. Epub 2020 Sep 29.

Corvus Pharmaceuticals, Burlingame, CA 94010, United States.

The immunosuppressive tumor microenvironment (TME) represents a challenge that all immunotherapies must overcome to enable a robust and durable anti-tumor response. One of the dominant mechanisms of immunosuppression in the TME is hypoxia and the generation of extracellular adenosine [1]. Pioneering work from Drs Ohta and Sitkovsky demonstrating that adenosine signaling through the adenosine 2A receptor (A2AR) inhibits T cells has led to the development of several agents designed to inhibit the production or downstream signaling of adenosine [2,3]. This review will focus on the safety, efficacy, and biomarkers associated with A2AR antagonists in clinical development.
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http://dx.doi.org/10.1016/j.coph.2020.08.003DOI Listing
August 2020

Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Department of Pathology, UM Medical School, Ann Arbor, Michigan, USA.

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effects of age and drug were sex dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength test. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth-promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids - changes that have previously been associated with aging, cardiac dysfunction, and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging antiaging effects in multiple tissues, and it may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.
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http://dx.doi.org/10.1172/jci.insight.137474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710286PMC
November 2020

Canagliflozin extends life span in genetically heterogeneous male but not female mice.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Sam and Ann Barshop Institute for Longevity and Aging Studies and Departments of Physiology and Molecular Medicine, UT Health San Antonio, San Antonio, Texas, USA; South Texas Veterans Healthcare System, San Antonio, Texas, USA.

Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
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http://dx.doi.org/10.1172/jci.insight.140019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710304PMC
November 2020

Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice.

Aging (Albany NY) 2020 05 28;12(10):8766-8789. Epub 2020 May 28.

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.

Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knock-out mice. We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.
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http://dx.doi.org/10.18632/aging.103380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288969PMC
May 2020

A Rare Case of Cutis Verticis Gyrata with Underlying Cerebriform Intradermal Nevus.

Cureus 2019 Dec 29;11(12):e6499. Epub 2019 Dec 29.

Dermatology, Hospital Corporation of America/University of South Florida, Morsani College of Medicine, Largo Medical Center Program, Largo, USA.

Cutis verticis gyrata (CVG) is an uncommon condition of the scalp known for redundant, thickened folds, which emulate the cerebral gyri of the brain. This unusual finding is catalogued as primary essential, primary non-essential, and secondary. While primary essential CVG is an isolated and idiopathic condition, primary non-essential CVG is deemed to be related to neurological, ophthalmological, or psychiatric disorders. Secondary CVG may be due to a variety of systemic disorders, inflammatory dermatoses, or cutaneous neoplasms or infiltrates. This report serves as an example of secondary CVG due to a cerebriform intradermal nevus, with specific focus on clinical course, treatment options, and critical screening guidelines for these patients.
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http://dx.doi.org/10.7759/cureus.6499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988481PMC
December 2019

Long-lived mice with reduced growth hormone signaling have a constitutive upregulation of hepatic chaperone-mediated autophagy.

Autophagy 2021 03 12;17(3):612-625. Epub 2020 Feb 12.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.

Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis. CMA modulates proteomic organization through selective protein degradation, with targets including metabolic enzymes, cell growth regulators, and neurodegeneration-related proteins. CMA activity is low in -fed rodents but is increased by prolonged fasting. AKT negatively regulates CMA at the lysosomal membrane by phosphorylating and inhibiting the CMA regulator GFAP. We have previously reported that long-lived mutant (Snell) mice and (growth hormone receptor) knockout mice ( KO) have lower AKT activity when fed compared to littermate controls, suggesting the hypothesis that these mice have increased baseline CMA activity. Here, we report that liver lysosomes from fed Snell dwarf mice and KO mice have decreased GFAP phosphorylation and increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell dwarf mice and KO mice injected with the protease inhibitor leupeptin had increased accumulation of endogenous CMA substrates, compared to littermate controls, suggesting an increase in CMA . Mice with liver-specific ablation of GH (growth hormone) signaling did not have increased liver CMA, suggesting that a signaling effect resulting from a loss of growth hormone in another tissue causes enhanced CMA in Snell dwarf and KO mice. Finally, we find Snell dwarf mice have decreased protein levels (in liver and kidney) of CIP2A, a well-characterized CMA target protein, without an associated change in mRNA. Collectively, these data suggest that CMA is enhanced downstream of an endocrine change resulting from whole-body ablation of GH signaling. CMA: chaperone-mediated autophagy; GH: growth hormone; KO: growth hormone receptor knockout; LAMP2A: splice variant 1 of transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li KO: liver-specific knockout; MA: macroautophagy; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; PBS: phosphate-buffered saline.
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http://dx.doi.org/10.1080/15548627.2020.1725378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032237PMC
March 2021

Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer.

Cancer Discov 2020 01 15;10(1):40-53. Epub 2019 Nov 15.

Corvus Pharmaceuticals, Burlingame, California.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954326PMC
January 2020

Genetic Support for Longevity-Enhancing Drug Targets: Issues, Preliminary Data, and Future Directions.

J Gerontol A Biol Sci Med Sci 2019 11;74(Suppl_1):S61-S71

Department of Quantitative Medicine and Systems Biology, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.

Interventions meant to promote longevity and healthy aging have often been designed or observed to modulate very specific gene or protein targets. If there are naturally occurring genetic variants in such a target that affect longevity as well as the molecular function of that target (eg, the variants influence the expression of the target, acting as "expression quantitative trait loci" or "eQTLs"), this could support a causal relationship between the pharmacologic modulation of the target and longevity and thereby validate the target at some level. We considered the gene targets of many pharmacologic interventions hypothesized to enhance human longevity and explored how many variants there are in those targets that affect gene function (eg, as expression quantitative trait loci). We also determined whether variants in genes associated with longevity-related phenotypes affect gene function or are in linkage disequilibrium with variants that do, and whether pharmacologic studies point to compounds exhibiting activity against those genes. Our results are somewhat ambiguous, suggesting that integrating genetic association study results with functional genomic and pharmacologic studies is necessary to shed light on genetically mediated targets for longevity-enhancing drugs. Such integration will require more sophisticated data sets, phenotypic definitions, and bioinformatics approaches to be useful.
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http://dx.doi.org/10.1093/gerona/glz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330475PMC
November 2019

Naturally occurring osteoarthritis in male mice with an extended lifespan.

Connect Tissue Res 2020 01 18;61(1):95-103. Epub 2019 Sep 18.

Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA.

: The purpose of this study was to evaluate whether pharmacologic treatments or genotypes shown to prolong murine lifespan ameliorate the severity of age-associated osteoarthritis.: Male UM-HET3 mice were fed diets containing 17-α-estradiol, acarbose, nordihydroguaiaretic acid, or control diet per the National Institute on Aging Interventions Testing Program (ITP) protocol. Findings were compared to genetically long-lived male Ames dwarf mice. Stifles were analyzed histologically with articular cartilage structure (ACS) and safranin O scoring as well as with quantitative histomorphometry.: Depending on the experimental group, ITP mice were between 450 and 1150 days old at the time of necropsy and 12-15 animals were studied per group. Two age groups (450 and 750 days) with 16-20 animals per group were used for Ames dwarf studies. No differences were found in the ACS or safranin O scores between treatment and control groups in the ITP study. There was high variability in most of the histologic outcome measures. For example, the older UM-HET3 controls had ACS scores of 6.1 ± 5.8 (mean±SD) and Saf O scores of 6.8 ± 5.6. Nevertheless, 17-α-estradiol mice had larger areas and widths of subchondral bone compared to controls, and dwarf mice had less subchondral bone area and width and less articular cartilage necrosis than non-dwarf controls.: UM-HET3 mice developed age-related OA but with a high degree of variability and without a significant effect of the tested ITP treatments. High variability was also seen in the Ames dwarf mice but differences in several measures suggested some protection from OA.
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http://dx.doi.org/10.1080/03008207.2019.1635590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884676PMC
January 2020

Improved mitochondrial stress response in long-lived Snell dwarf mice.

Aging Cell 2019 12 18;18(6):e13030. Epub 2019 Aug 18.

Department of Molecular and Cellular Pathology, University of Michigan Geriatrics Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.

Prolonged lifespan and improved health in late adulthood can be achieved by partial inhibition of mitochondrial proteins in yeast, worms, fruit flies, and mice. Upregulation of the mitochondrial unfolded protein response (mtUPR) has been proposed as a common pathway in lifespan extension induced by mitochondrial defects. However, it is not known whether mtUPR is elevated in long-lived mouse models. Here, we report that Snell dwarf mice, which show 30%-40% lifespan extension and prolonged healthspan, exhibit augmented mitochondrial stress responses. Cultured cells from Snell mice show elevated levels of the mitochondrial chaperone HSP60 and mitochondrial protease LONP1, two components of the mtUPR. In response to mitochondrial stress, the increase in Tfam (mitochondrial transcription factor A), a regulator of mitochondrial transcription, is higher in Snell cells, while Pgc-1α, the main regulator of mitochondrial biogenesis, is upregulated only in Snell cells. Consistent with these differences, Snell cells maintain oxidative respiration rate, ATP content, and expression of mitochondrial-DNA-encoded genes after exposure to doxycycline stress. In vivo, compared to normal mice, Snell mice show stronger hepatic mtUPR induction and maintain mitochondrial protein stoichiometry after mitochondrial stress exposure. Overall, our work demonstrates that a long-lived mouse model exhibits improved mitochondrial stress response, and provides a rationale for future mouse lifespan studies involving compounds that induce mtUPR. Further research on mitochondrial homeostasis in long-lived mice may facilitate development of interventions that blunt mitochondrial deterioration in neurodegenerative diseases such as Alzheimer's and Parkinson's and postpone diseases of aging in humans.
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http://dx.doi.org/10.1111/acel.13030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826134PMC
December 2019

Mitochondrial DNA alterations in aged macrophage migration inhibitory factor-knockout mice.

Mech Ageing Dev 2019 09 2;182:111126. Epub 2019 Aug 2.

Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, CA, USA. Electronic address:

The age-induced, exponential accumulation of mitochondrial DNA (mtDNA) deletion mutations contributes to muscle fiber loss. The causes of these mutations are not known. Systemic inflammation is associated with decreased muscle mass in older adults and is implicated in the formation of sporadic mtDNA deletions. Macrophage migration inhibitory factor knockout (MIF-KO) mice are long-lived with decreased inflammation. We hypothesized that aged MIF-KO mice would have lower mtDNA deletion frequencies and fewer electron transport chain (ETC) deficient fibers. We measured mtDNA copy number and mutation frequency as well as the number and length of ETC deficient fibers in 22-month old MIF-KO and F2 hybrid control mice. We also measured mtDNA copy number and deletion frequency in female UM-HET3 mice, a strain whose lifespan matches the MIF-KO mice. We did not observe a significant effect of MIF ablation on muscle mtDNA deletion frequency. There was a significantly lower mtDNA copy number in the MIF-KO mice and the lifespan-matched UM-HET3 mice compared to the F2 hybrids, suggesting the importance of genetic background in mtDNA copy number control. Our data do not support a definitive role for MIF in age-induced mtDNA deletions.
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http://dx.doi.org/10.1016/j.mad.2019.111126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718337PMC
September 2019

Cap-independent mRNA translation is upregulated in long-lived endocrine mutant mice.

J Mol Endocrinol 2019 08;63(2):123-138

Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

It has been hypothesized that transcriptional changes associated with lower mTORC1 activity in mice with reduced levels of growth hormone and insulin-like growth factor 1 are responsible for the longer healthy lifespan of these mutant mice. Cell lines and tissues from these mice show alterations in the levels of many proteins that cannot be explained by corresponding changes in mRNAs. Such post-transcriptional modulation may be the result of preferential mRNA translation by the cap-independent translation of mRNA bearing the N6-methyl-adenosine (m6A) modification. The long-lived endocrine mutants - Snell dwarf, growth hormone receptor deletion and pregnancy-associated plasma protein-A knockout - all show increases in the N6-adenosine-methyltransferases (METTL3/14) that catalyze 6-methylation of adenosine (m6A) in the 5' UTR region of select mRNAs. In addition, these mice have elevated levels of YTH domain-containing protein 1 (YTHDF1), which recognizes m6A and promotes translation by a cap-independent mechanism. Consistently, multiple proteins that can be translated by the cap-independent mechanism are found to increase in these mice, including DNA repair and mitochondrial stress response proteins, without changes in corresponding mRNA levels. Lastly, a drug that augments cap-independent translation by inhibition of cap-dependent pathways (4EGI-1) was found to elevate levels of the same set of proteins and able to render cells resistant to several forms of in vitro stress. Augmented translation by cap-independent pathways facilitated by m6A modifications may contribute to the stress resistance and increased healthy longevity of mice with diminished GH and IGF-1 signals.
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http://dx.doi.org/10.1530/JME-19-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691957PMC
August 2019

Life-span Extension Drug Interventions Affect Adipose Tissue Inflammation in Aging.

J Gerontol A Biol Sci Med Sci 2020 01;75(1):89-98

Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor.

The National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP) has identified a number of dietary drug interventions that significantly extend life span, including rapamycin, acarbose, and 17-α estradiol. However, these drugs have diverse downstream targets, and their effects on age-associated organ-specific changes are unclear (Nadon NL, Strong R, Miller RA, Harrison DE. NIA Interventions Testing Program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine. 2017;21:3-4. doi:10.1016/j.ebiom.2016.11.038). Potential mechanisms by which these drugs extend life could be through their effect on inflammatory processes often noted in tissues of aging mice and humans. Our study focuses on the effects of three drugs in the ITP on inflammation in gonadal white adipose tissue (gWAT) of HET3 mice-including adiposity, adipose tissue macrophage (ATM) M1/M2 polarization, markers of cellular senescence, and endoplasmic reticulum stress. We found that rapamycin led to a 56% increase of CD45+ leukocytes in gWAT, where the majority of these are ATMs. Interestingly, rapamycin led to a 217% and 106% increase of M1 (CD45+CD64+CD206-) ATMs in females and males, respectively. Our data suggest rapamycin may achieve life-span extension in part through adipose tissue inflammation. Additionally, HET3 mice exhibit a spectrum of age-associated changes in the gWAT, but acarbose and 17-α estradiol do not strongly alter these phenotypes-suggesting that acarbose and 17- α estradiol may not influence life span through mechanisms involving adipose tissue inflammation.
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http://dx.doi.org/10.1093/gerona/glz177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909899PMC
January 2020

Identification and Application of Gene Expression Signatures Associated with Lifespan Extension.

Cell Metab 2019 09 25;30(3):573-593.e8. Epub 2019 Jul 25.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA, USA. Electronic address:

Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing (RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.
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http://dx.doi.org/10.1016/j.cmet.2019.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907080PMC
September 2019

Case Report: Kryptonite-A Rare Case of Left-Sided Bilothorax in a Sickle Cell Patient.

Case Rep Pulmonol 2019 18;2019:8658343. Epub 2019 Jun 18.

Department of Gastroenterology, Saint Michael's Medical Center, Newark, NJ, USA.

Bilothorax is a rare cause of an exudative pleural effusion. The diagnosis is confirmed by a pleural fluid to serum bilirubin ratio of greater than 1. Typically, bilothorax presents as a right-sided effusion due to its proximity to the liver and biliary system. Herein, we present a case of isolated left-sided bilothorax in a 43-year-old female admitted with sickle cell crisis. Only one other case of isolated spontaneous left-sided bilothorax has been described in the literature. A thoracentesis performed on admission demonstrated greenish fluid and bilothorax was suspected, with a pleural fluid to serum bilirubin ratio greater than 1 confirming the diagnosis. A magnetic resonance cholangiopancreatography (MRCP) showed an abnormal 90-degree acute angulation in the mid-to-distal common bile duct with proximal common bile duct and intrahepatic bile ducts dilation. This was further confirmed with an endoscopic retrograde cholangiopancreatography (ERCP), which did not reveal any extravasation of contrast into the left pleural space. Ultimately, despite the use of various modalities, no definitive cause of bilothorax was identified. Postthoracentesis imaging revealed evidence of fibrothorax, a direct and permanent complication of bilothorax. The presence of an isolated left-sided bilothorax, along with the lack of a confirmed etiology, makes this case unique.
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http://dx.doi.org/10.1155/2019/8658343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604467PMC
June 2019

Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice.

BMC Microbiol 2019 06 13;19(1):130. Epub 2019 Jun 13.

Department of Ecology & Evolutionary Biology, University of Michigan, Ann Arbor, 48109, MI, USA.

Background: Treatment with the α-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to increased longevity in mice. To explore this hypothesis, we compared the fecal microbiome of mice treated with acarbose to control mice at three independent study sites.

Results: Microbial communities and the concentrations of SCFAs in the feces of mice treated with acarbose were notably different from those of control mice. At all three study sites, the bloom of a single bacterial taxon was the most obvious response to acarbose treatment. The blooming populations were classified to the largely uncultured Bacteroidales family Muribaculaceae and were the same taxonomic unit at two of the three sites. Propionate concentrations in feces were consistently elevated in treated mice, while the concentrations of acetate and butyrate reflected a dependence on study site. Across all samples, Muribaculaceae abundance was strongly correlated with propionate and community composition was an important predictor of SCFA concentrations. Cox proportional hazards regression showed that the fecal concentrations of acetate, butyrate, and propionate were, together, predictive of mouse longevity even while controlling for sex, site, and acarbose.

Conclusion: We observed a correlation between fecal SCFAs and lifespan in mice, suggesting a role of the gut microbiota in the longevity-enhancing properties of acarbose. Treatment modulated the taxonomic composition and fermentation products of the gut microbiome, while the site-dependence of the responses illustrate the challenges facing reproducibility and interpretation in microbiome studies. These results motivate future studies exploring manipulation of the gut microbial community and its fermentation products for increased longevity, testing causal roles of SCFAs in the observed effects of acarbose.
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http://dx.doi.org/10.1186/s12866-019-1494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567620PMC
June 2019

Cellular energetics and mitochondrial uncoupling in canine aging.

Geroscience 2019 04 1;41(2):229-242. Epub 2019 Apr 1.

Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14850, USA.

The first domesticated companion animal, the dog, is currently represented by over 190 unique breeds. Across these numerous breeds, dogs have exceptional variation in lifespan (inversely correlated with body size), presenting an opportunity to discover longevity-determining traits. We performed a genome-wide association study on 4169 canines representing 110 breeds and identified novel candidate regulators of longevity. Interestingly, known functions within the identified genes included control of coat phenotypes such as hair length, as well as mitochondrial properties, suggesting that thermoregulation and mitochondrial bioenergetics play a role in lifespan variation. Using primary dermal fibroblasts, we investigated mitochondrial properties of short-lived (large) and long-lived (small) dog breeds. We found that cells from long-lived breeds have more uncoupled mitochondria, less electron escape, greater respiration, and capacity for respiration. Moreover, our data suggest that long-lived breeds have higher rates of catabolism and β-oxidation, likely to meet elevated respiration and electron demand of their uncoupled mitochondria. Conversely, cells of short-lived (large) breeds may accumulate amino acids and fatty acid derivatives, which are likely used for biosynthesis and growth. We hypothesize that the uncoupled metabolic profile of long-lived breeds likely stems from their smaller size, reduced volume-to-surface area ratio, and therefore a greater need for thermogenesis. The uncoupled energetics of long-lived breeds lowers reactive oxygen species levels, promotes cellular stress tolerance, and may even prevent stiffening of the actin cytoskeleton. We propose that these cellular characteristics delay tissue dysfunction, disease, and death in long-lived dog breeds, contributing to canine aging diversity.
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http://dx.doi.org/10.1007/s11357-019-00062-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544733PMC
April 2019

mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism.

Aging Cell 2019 06 29;18(3):e12943. Epub 2019 Mar 29.

Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California.

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.
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http://dx.doi.org/10.1111/acel.12943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516169PMC
June 2019

Glycine supplementation extends lifespan of male and female mice.

Aging Cell 2019 06 27;18(3):e12953. Epub 2019 Mar 27.

Department of Pharmacology, Barshop Institute for Longevity and Aging Studies, Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males. End-of-life necropsies suggested that glycine-treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine-supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI-1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.
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http://dx.doi.org/10.1111/acel.12953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516426PMC
June 2019

Brain Protein Synthesis Rates in the UM-HET3 Mouse Following Treatment With Rapamycin or Rapamycin With Metformin.

J Gerontol A Biol Sci Med Sci 2020 01;75(1):40-49

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City.

Treatment with the mechanistic target of rapamycin (mTOR) inhibitor, rapamycin (RAP), alone and in combination with the antidiabetic drug, metformin (RAP+MET), extends lifespan in mice. The mechanisms underlying lifespan extension are unclear. One possibility is improved capacity for proteostatic maintenance. We have previously characterized peripheral protein synthesis rates following treatment with RAP. However, it is unknown if RAP+MET elicits similar changes, or if either treatment affects protein synthesis in the brain. We hypothesized that 8 weeks of treatment with RAP and RAP+MET would alter brain protein synthesis rates to reflect proteostatic processes. Using the stable isotopic tracer, deuterium oxide (D2O), we demonstrate in UM-HET3 mice that protein synthesis rates measured in whole brain were unaffected by treatment in young male mice, whereas RAP+MET decreased mitochondrial protein synthesis in young females. Conversely, RAP increased mitochondrial protein synthesis rates in older females. Activity through the AMPK/mTOR pathway was affected in a sex-specific manner in young mice, and minimal changes were observed in the older cohort. Thus, we establish D2O for measurements of biogenesis in the brain. These results provide initial insights into the effects of RAP and RAP+MET on brain protein synthesis. Additionally, these data emphasize that responses to slowed aging treatments vary with sex and age.
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http://dx.doi.org/10.1093/gerona/glz069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175973PMC
January 2020

17-α estradiol ameliorates age-associated sarcopenia and improves late-life physical function in male mice but not in females or castrated males.

Aging Cell 2019 04 10;18(2):e12920. Epub 2019 Feb 10.

Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.

Pharmacological treatments can extend mouse lifespan, but lifespan effects often differ between sexes. 17-α estradiol (17aE2), a less feminizing structural isomer of 17-β estradiol, produces lifespan extension only in male mice, suggesting a sexually dimorphic mechanism of lifespan regulation. We tested whether these anti-aging effects extend to anatomical and functional aging-important in late-life health-and whether gonadally derived hormones control aging responses to 17aE2 in either sex. While 17aE2 started at 4 months of age diminishes body weight in both sexes during adulthood, in late-life 17aE2-treated mice better maintain body weight. In 17aE2-treated male mice, the higher body weight is associated with heavier skeletal muscles and larger muscle fibers compared with untreated mice during aging, while treated females have heavier subcutaneous fat. Maintenance of skeletal muscle in male mice is associated with improved grip strength and rotarod capacity at 25 months, in addition to higher levels of most amino acids in quadriceps muscle. We further show that sex-specific responses to 17aE2-metabolomic, structural, and functional-are regulated by gonadal hormones in male mice. Castrated males have heavier quadriceps than intact males at 25 months, but do not respond to 17aE2, suggesting 17aE2 promotes an anti-aging skeletal muscle phenotype similar to castration. Finally, 17aE2 treatment benefits can be recapitulated in mice when treatment is started at 16 months, suggesting that 17aE2 may be able to improve aspects of late-life function even when started after middle age.
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http://dx.doi.org/10.1111/acel.12920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413653PMC
April 2019

Acarbose improves health and lifespan in aging HET3 mice.

Aging Cell 2019 04 27;18(2):e12898. Epub 2019 Jan 27.

Department of Pathology, University of Michigan, Ann Arbor, Michigan.

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%-11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans.
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http://dx.doi.org/10.1111/acel.12898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413665PMC
April 2019