APOE2 is associated with longevity independent of Alzheimer's disease
- National Center for Geriatrics and Gerontology, Japan
- Mayo Clinic, United States
- University of Texas Health Science Center at San Antonio, United States
- Durham Veterans Health Administration Medical Center's Geriatric Research, United States
- Georgetown University Medical Center, United States
Abstract
Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer's disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity. Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical database as well as animal models. Notably, APOE2 was associated with preserved physical activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. These results indicate that APOE2 can contribute to longevity independent of AD. Preserved activity would be an early-observable feature of apoE2-mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved.
Data availability
All source data files of animal experiments (Figure 2, Figure 4, Supplementary File 1d, and Supplementary File 1f) are included in the manuscript and supporting files. The clinical data are available from NACC (https://www.alz.washington.edu/WEB/researcher_home.html) upon request: distributing any data to a third party, who is not a collaborator or co-authors, is strictly prohibited by NACC.
Article and author information
Author details
Funding
National Institute on Aging (RF1AG057181)
- Guojun Bu
Naito Foundation
- Mitsuru Shinohara
BrightFocus Foundation
- Mitsuru Shinohara
National Center for Geriatrics and Gerontology
- Mitsuru Shinohara
Hori Sciences and Arts Foundation
- Mitsuru Shinohara
National Institute on Aging (R37AG027924)
- Guojun Bu
National Institute on Aging (R01AG046205)
- Guojun Bu
National Institute on Aging (RF1AG051504)
- Guojun Bu
National Institute on Aging (P01NS074969)
- Guojun Bu
National Institute on Aging (P30AG062677)
- Guojun Bu
Cure Alzheimer's Fund
- Guojun Bu
National Institute on Aging (R21AG052423)
- Takahisa Kanekiyo
Japan Heart Foundation
- Mitsuru Shinohara
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Rudolph E Tanzi, Harvard University, United States
Ethics
Animal experimentation: All cohorts examined in this study were generated from homozygous breeding pairs, group housed without enrichment structures in a specific pathogen-free environment in ventilated cages and used in experiments according to the standards established by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC, Protocol# A58312).
Version history
- Received: August 17, 2020
- Accepted: October 13, 2020
- Accepted Manuscript published: October 19, 2020 (version 1)
- Version of Record published: October 26, 2020 (version 2)
Copyright
© 2020, Shinohara et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,252
- views
-
- 519
- downloads
-
- 42
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
APOE2 is associated with longevity independent of Alzheimer's disease
eLife 9:e62199.
https://doi.org/10.7554/eLife.62199
Further reading
-
- Developmental Biology
- Medicine
From a forward mutagenetic screen to discover mutations associated with obesity, we identified mutations in the Spag7 gene linked to metabolic dysfunction in mice. Here, we show that SPAG7 KO mice are born smaller and develop obesity and glucose intolerance in adulthood. This obesity does not stem from hyperphagia, but a decrease in energy expenditure. The KO animals also display reduced exercise tolerance and muscle function due to impaired mitochondrial function. Furthermore, SPAG7-deficiency in developing embryos leads to intrauterine growth restriction, brought on by placental insufficiency, likely due to abnormal development of the placental junctional zone. This insufficiency leads to loss of SPAG7-deficient fetuses in utero and reduced birth weights of those that survive. We hypothesize that a ‘thrifty phenotype’ is ingrained in SPAG7 KO animals during development that leads to adult obesity. Collectively, these results indicate that SPAG7 is essential for embryonic development and energy homeostasis later in life.
-
- Medicine
Background:
The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing.
Methods:
Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.
Results:
Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182–5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182–5 p overexpression. Weight loss in obese mice decreased hepatic miR-182–5 p and restored Lrp6 expression and other miR-182–5 p target genes. Hepatic overexpression of miR-182–5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.
Conclusions:
By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182–5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182–5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.
Funding:
This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G).
