Rare genetic coding variants associated with human longevity and protection against age-related diseases

Lin, Jhih-Rong; Sin‐Chan, Patrick; Napolioni, Valerio; Torres, Guillermo G.; Mitra, Joydeep; Zhang, Quanwei; Jabalameli, M. Reza; Wang, Zhen; Nguyen, Nha; Gao, Ting; Laudes, Matthias; Görg, Siegfried; Franke, André; Nebel, Almut; Greicius, Michael D.; Atzmon, Gil; Ye, Kenny; Gorbunova, Vera; Ladiges, Warren; Shuldiner, Alan R.; Niedernhofer, Laura J.; Robbins, Paul D.; Milman, Sofiya; Suh, Yousin; Vijg, Jan; Barzilai, Nir; Zhang, Zhengdong D.

doi:10.1038/s43587-021-00108-5

Cited by 29 publications

(30 citation statements)

References 74 publications

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“…The literature supports a link between disease-associated variants and human longevity, within and beyond the TOMM40/APOE/APOC1 gene region [14,19,26,27]. Our results substantiated the relatively well-documented shared genetic component of longevity and predisposition to cardiovascular disease (CVD; significantly lower risk scores for CAD, AF and ISS in LLI compared to controls) as well as the genetic link with AD [14,15,[18][19][20]28]. Additionally, we strengthened the evidence of a shared genetic architecture between longevity and T2D, as already indicated in, e.g., [15,20].…”

Section: Discussionsupporting

confidence: 85%

“…Our results substantiated the relatively well-documented shared genetic component of longevity and predisposition to cardiovascular disease (CVD; significantly lower risk scores for CAD, AF and ISS in LLI compared to controls) as well as the genetic link with AD [14,15,[18][19][20]28]. Additionally, we strengthened the evidence of a shared genetic architecture between longevity and T2D, as already indicated in, e.g., [15,20]. Moreover, the German LLI exhibited a lower PRS for CRC than the younger controls, supporting that the lower CRC prevalence, incidence and mortality in centenarians [29] has, at least in part, a genetic basis [30].…”

Section: Discussionsupporting

confidence: 85%

“…They reported a large genetic overlap between longevity and AD and CAD, respectively, which is supported by other studies (e.g., [15,[18][19][20]). For other ARDs, such as T2D, the evidence for a possible genetic link with human longevity is less clear (see, e.g., [14,15,20,21]).…”

Section: Introductionsupporting

confidence: 79%

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Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

Torres

Dose

Hasenbein

et al. 2022

IJMS

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Longevity is a complex phenotype influenced by both environmental and genetic factors. The genetic contribution is estimated at about 25%. Despite extensive research efforts, only a few longevity genes have been validated across populations. Long-lived individuals (LLI) reach extreme ages with a relative low prevalence of chronic disability and major age-related diseases (ARDs). We tested whether the protection from ARDs in LLI can partly be attributed to genetic factors by calculating polygenic risk scores (PRSs) for seven common late-life diseases (Alzheimer’s disease (AD), atrial fibrillation (AF), coronary artery disease (CAD), colorectal cancer (CRC), ischemic stroke (ISS), Parkinson’s disease (PD) and type 2 diabetes (T2D)). The examined sample comprised 1351 German LLI (≥94 years, including 643 centenarians) and 4680 German younger controls. For all ARD-PRSs tested, the LLI had significantly lower scores than the younger control individuals (areas under the curve (AUCs): ISS = 0.59, p = 2.84 × 10−35; AD = 0.59, p = 3.16 × 10−25; AF = 0.57, p = 1.07 × 10−16; CAD = 0.56, p = 1.88 × 10−12; CRC = 0.52, p = 5.85 × 10−3; PD = 0.52, p = 1.91 × 10−3; T2D = 0.51, p = 2.61 × 10−3). We combined the individual ARD-PRSs into a meta-PRS (AUC = 0.64, p = 6.45 × 10−15). We also generated two genome-wide polygenic scores for longevity, one with and one without the TOMM40/APOE/APOC1 gene region (AUC (incl. TOMM40/APOE/APOC1) = 0.56, p = 1.45 × 10−5, seven variants; AUC (excl. TOMM40/APOE/APOC1) = 0.55, p = 9.85 × 10−3, 10,361 variants). Furthermore, the inclusion of nine markers from the excluded region (not in LD with each other) plus the APOE haplotype into the model raised the AUC from 0.55 to 0.61. Thus, our results highlight the importance of TOMM40/APOE/APOC1 as a longevity hub.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

Torres

Dose

Hasenbein

et al. 2022

IJMS

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“…There are now different biotech start-ups focused on antiaging therapies (Dolgin, 2021;Regalado, 2021). In the laboratory and beyond, the underlying biology of aging in humans and other species is under intense scrutiny (Augustin & Kipnis, 2021;Fan et al, 2017;Garcia et al, 2021b;Gorbunova et al, 2021;Grunewald et al, 2021;Hägg & Jylhävä, 2021;Lengefeld et al, 2021;Lin et al, 2021b;Lu et al, 2021c;Martinez-Miguel et al, 2021;Sato et al, 2022;Stein et al, 2022;Vidal-Pineiro et al, 2021;Wang & Blau, 2021;Wiley & Campisi, 2021). These projects pursue many different exciting threads, including the so-called "senotherapeutics" (Robbins et al, 2021); the relationship between aging and the microbiome (Rimal & Patterson, 2021;Sato et al, 2021;Shukla et al, 2021); biological constraints on the rate of human aging (Colchero et al, 2021); the effects of physical activity on aging (Horowitz et al, 2020;Lieberman et al, 2021); the effect of dietary polyamines (Schroeder et al, 2021), fasting (Helfand & de Cabo, 2021;Ulgherait et al, 2021), and the efficacy of supposed "antiaging diets" in general (Lee et al, 2021;Longo & Anderson, 2022); the role of the immune system (Yousefzadeh et al, 2021); the social aspects of healthy aging (Charles et al, 2021;Hanc, 2021;Savage, 2022); and the economics of treatments that target aging (Scott et al, 2021).…”

Section: Longevity and Agingmentioning

confidence: 99%

Introduction: Trends, Puzzles, and Hopes for the Future of Healthcare

Ehsani

Glauner

Plugmann

et al. 2022

Future of Business and Finance

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This book is being published at a time when the collective attention of the world has been focused, for more than 2 years, on the coronavirus pandemic. The interrelatedness of various facets of biomedicine (whether scientific, societal, political, legal, or cultural) has been vividly illustrated to health practitioners, researchers, and the public at large—often on a very personal level. It is now manifestly obvious to many that planning for the future of clinical and experimental medicine is a must. Although the task of predicting the exact trajectory of any profession might be in vain, it is essential that one at least looks at past and current trends in order to envision future scenarios and plan for them. We can thus shape our expectations about how the various threads of biomedicine could develop; these could then inform our preparedness.

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“…Due to its high evolutionary conservation, IIS has also been suggested to be involved in human longevity. Indeed, recent genome wide association studies have implicated variants in IIS pathway loci with longevity( 11 ), and studies of rare genetic variants have found enrichment of IIS variants in centenarians, suggesting a relationship between IIS and longevity in humans( 12 ). The finding that a longevity-associated allele from humans reduces IIS activity in cell culture(13) further supports this link.…”

Section: Introductionmentioning

confidence: 99%

Reduced insulin signalling in neurons induces sex-specific health benefits

Baghdadi

Nespital

Mesaros

et al. 2022

Preprint

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Reduced activity of the insulin/IGF signalling (IIS) network extends healthspan and lifespan in mammals and possibly humans. Loss of the Irs1 gene increases survival in mice and causes tissue-specific changes in gene expression. However, the tissues underlying IIS mediated longevity are currently unknown. Here we measured survival and healthspan in male and female animals lacking Irs1 activity specifically in the liver, muscle, fat and brain. Tissue-specific loss of IRS1 did not increase survival, suggesting that lack of Irs1 in more than one tissue is required for lifespan extension. Furthermore, loss of Irs1 in liver, muscle and fat did not improve health at old age. In contrast, loss of neuronal Irs1 increased energy expenditure, locomotion and insulin sensitivity, specifically in old males. Neuronal loss of IRS1 also caused male-specific mitochondrial dysfunction, activation of Atf4 and metabolic adaptations consistent with an activated integrated stress response at old age. Thus, we identified a male-specific brain signature of ageing in response to reduced IIS associated with improved health outcomes at old age.

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Rare genetic coding variants associated with human longevity and protection against age-related diseases

Cited by 29 publications

References 74 publications

Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

Introduction: Trends, Puzzles, and Hopes for the Future of Healthcare

Reduced insulin signalling in neurons induces sex-specific health benefits

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