Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

Abstract:

:Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

journal_name

Biogerontology

journal_title

Biogerontology

authors

Ukraintseva S,Yashin A,Arbeev K,Kulminski A,Akushevich I,Wu D,Joshi G,Land KC,Stallard E

doi

10.1007/s10522-015-9600-1

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

109-27

issue

1

eissn

1389-5729

issn

1573-6768

pii

10.1007/s10522-015-9600-1

journal_volume

17

pub_type

杂志文章,评审
  • Human ageing and the origins of religion.

    abstract::During the evolution of hominids, the population could be sustained even with an expectation of life at birth of less than 20 years. Under these circumstances very few individuals reached old age. In these hunter-gatherer communities, altruistic behaviour was encouraged because it increased the likelihood of survival,...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1023/a:1010004901256

    authors: Holliday R

    更新日期:2001-01-01 00:00:00

  • Background radiation impacts human longevity and cancer mortality: reconsidering the linear no-threshold paradigm.

    abstract::The current linear no-threshold paradigm assumes that any exposure to ionizing radiation carries some risk, thus every effort should be made to maintain the exposures as low as possible. We examined whether background radiation impacts human longevity and cancer mortality. Our data covered the entire US population of ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-020-09909-4

    authors: David E,Wolfson M,Fraifeld VE

    更新日期:2021-01-22 00:00:00

  • Glycerol stimulates innate chaperoning, proteasomal and stress-resistance functions: implications for geronto-manipulation.

    abstract::Aging is associated with accumulation of toxic intracellular and extracellular protein aggregates. Cells manage "aged" proteins by mobilizing their molecular chaperones or heat shock proteins that are also considered as determinants of lifespan in diverse species. In this study, we tested whether an exogenous addition...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-008-9136-8

    authors: Deocaris CC,Takano S,Priyandoko D,Kaul Z,Yaguchi T,Kraft DC,Yamasaki K,Kaul SC,Wadhwa R

    更新日期:2008-08-01 00:00:00

  • Effect of chronic treatments with GH, melatonin, estrogens, and phytoestrogens on oxidative stress parameters in liver from aged female rats.

    abstract::The aging theory postulates that this process may be due to the accumulation of oxidative damage in cells and molecules. The present study has investigated the effect of castration in old female rats on various parameters related to the antioxidant properties of several cellular fractions obtained from the liver, and ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-007-9089-3

    authors: Kireev RA,Tresguerres AF,Vara E,Ariznavarreta C,Tresguerres JA

    更新日期:2007-10-01 00:00:00

  • Age-related alterations of Apolipoprotein E and interleukin-1beta in the aging brain.

    abstract::With normal aging, the brain undergoes several alterations including reduced neuronal functioning and alterations in glia homeostasis. An increase in inflammatory signaling has also been reported in some studies of the aging brain, with inflammation potentially mediating age-related changes in the brain. Apolipoprotei...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-005-6039-9

    authors: Gee JR,Ding Q,Keller JN

    更新日期:2006-04-01 00:00:00

  • Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population.

    abstract::Associations have been reported between plasma Cu and Zn levels and the incidence of the most important age-related diseases. Previously proposed methods of using plasma Cu/Zn as a predictor of all-cause mortality have been derived from populations in which old and very old subjects were underrepresented. The purpose ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-009-9251-1

    authors: Malavolta M,Giacconi R,Piacenza F,Santarelli L,Cipriano C,Costarelli L,Tesei S,Pierpaoli S,Basso A,Galeazzi R,Lattanzio F,Mocchegiani E

    更新日期:2010-06-01 00:00:00

  • An inverse-Warburg effect and the origin of Alzheimer's disease.

    abstract::Glycolysis and oxidative phosphorylation (OxPhos) are the two major mechanisms involved in brain energetics. In this article we propose that the sporadic forms of Alzheimer's disease (AD) are driven by age-related damage to macromolecules and organelles which results in the following series of dynamic processes. (1) M...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-012-9403-6

    authors: Demetrius LA,Simon DK

    更新日期:2012-12-01 00:00:00

  • Sex hormones and skeletal muscle weakness.

    abstract::Human ageing is accompanied with deterioration in endocrine functions the most notable and well characterized of which being the decrease in the production of sex hormones. Current research literature suggests that low sex hormone concentration may be among the key mechanism for sarcopenia and muscle weakness. Within ...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1007/s10522-013-9425-8

    authors: Sipilä S,Narici M,Kjaer M,Pöllänen E,Atkinson RA,Hansen M,Kovanen V

    更新日期:2013-06-01 00:00:00

  • Genetic background, epigenetic factors and dietary interventions which influence human longevity.

    abstract::Longevity is mainly conditioned by genetic, epigenetic and environmental factors. Different genetic modifications seem to be positively associated to longevity, including SNPs in SIRT1, APOE, FOXO3A, ACE, ATM, NOS1 and NOS2 gene. Epigenetic changes as DNA hyper- and hypo-methylation influence significantly human longe...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1007/s10522-019-09824-3

    authors: Costa D,Scognamiglio M,Fiorito C,Benincasa G,Napoli C

    更新日期:2019-10-01 00:00:00

  • Protein degradation during aging: the lysosome-, the calpain- and the proteasome-dependent cellular proteolytic systems.

    abstract::Aging is a natural process determined by both genetic and environmental factors. Aging is accompanied by the imbalance of the function of several cellular homeostatic mechanisms, which results, among others, in the accumulation of abnormal (i.e. oxidized, cross-linked, unfolded) proteins. It has been proposed that the...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1023/a:1015236203379

    authors: Chondrogianni N,Fragoulis EG,Gonos ES

    更新日期:2002-01-01 00:00:00

  • Daily NO rhythms in peripheral clocks in aging male Wistar rats: protective effects of exogenous melatonin.

    abstract::In mammals suprachiasmatic nucleus (SCN), acts as a light entrainable master clock and by generation of temporal oscillations regulates the peripheral organs acting as autonomous clocks resulting in overt behavioral and physiological rhythms. SCN also controls synthesis and release of melatonin (hormonal message for d...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-016-9656-6

    authors: Vinod C,Jagota A

    更新日期:2016-11-01 00:00:00

  • Life extension in Drosophila maintained under lengthened light/dark regime.

    abstract::In the present study, we investigated whether the length of light/dark cycle could influence the pre-adult developmental time and adult life span in Drosophila melanogaster. Flies were reared to adulthood and maintained as adults under both 24-h (light/dark 12:12 h) and 48-h (light/dark 24:24 h) cycles. The flies rear...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-008-9146-6

    authors: Vaiserman AM,Pisaruck AV,Timchenko AN,Voitenko VP,Koshel NM,Grigoriev PE

    更新日期:2008-10-01 00:00:00

  • Mitochondria, its DNA and telomeres in ageing and human population.

    abstract::In the last decades, studies about ageing have become more essential as our population grows older. The incidence of age-related diseases increases, which pose challenges both for societies and individuals in terms of life quality and economic impact. Understanding ageing and ageing-related processes will help us to s...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1007/s10522-018-9748-6

    authors: Zole E,Ranka R

    更新日期:2018-07-01 00:00:00

  • Quercetin mediated lifespan extension in Caenorhabditis elegans is modulated by age-1, daf-2, sek-1 and unc-43.

    abstract::The nematode Caenorhabditis elegans responds to flavonoid-rich diets with improved health and longevity. The precise mechanism(s) responsible for this remains to be identified, but is believed to be linked to the highly antioxidative properties of flavonoids. This study provides a dissection of lifespan modulation by ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-008-9199-6

    authors: Pietsch K,Saul N,Menzel R,Stürzenbaum SR,Steinberg CE

    更新日期:2009-10-01 00:00:00

  • Dysregulations of mitochondrial quality control and autophagic flux at an early age lead to progression of sarcopenia in SAMP8 mice.

    abstract::The senescence-accelerated mouse (SAM) prone 8 (SAMP8) has been demonstrated for muscular aging research including sarcopenia, but its underlying mechanisms remain scarce. Physiological indices and histology of skeletal muscle were analyzed in SAMP8 mice at different ages. SAMP8 mice exhibited typical features of sarc...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-020-09867-x

    authors: Liu HW,Chang YC,Chan YC,Hu SH,Liu MY,Chang SJ

    更新日期:2020-06-01 00:00:00

  • Resistance to oxidative stress induced by paraquat correlates well with both decreased and increased lifespan in Drosophila melanogaster.

    abstract::There is increasing support for the notion that genetic variation for lifespan, both within and between species, is correlated with variation in the efficiency of the free radical scavenging system and the ability to withstand oxidative stress. In Drosophila, resistance to dietary paraquat, a free radical generator, i...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-005-4903-2

    authors: Vermeulen CJ,Van De Zande L,Bijlsma R

    更新日期:2005-12-01 00:00:00

  • L-Carnitine inhibits the senescence-associated secretory phenotype of aging adipose tissue by JNK/p53 pathway.

    abstract::Senescence-associated secretory phenotype (SASP) plays a role in aging adipose tissue dysfunction by directly promoting chronic inflammation. The JNK/p53 pathway was reported as a potential mechanism that mediates SASP. In this study, we investigated the effects of L-carnitine, an inhibitor of the JNK/p53 pathway in a...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-018-9787-z

    authors: Yang LW,Song M,Li YL,Liu YP,Liu C,Han L,Wang ZH,Zhang W,Xing YQ,Zhong M

    更新日期:2019-04-01 00:00:00

  • The RESOLVE concept: approaching pathophysiology of fibroproliferative disease in aged individuals.

    abstract::After reaching adulthood, orderly repair is probably one of the most important mechanisms throughout lifetime. Regular wound healing after an injury consists of a well-ordered sequence of overlapping phases of repair and essentially repeats the complex process of organ development. Organ failure in the ageing organism...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1007/s10522-013-9453-4

    authors: Ziesche R,Golec M,Samaha E

    更新日期:2013-12-01 00:00:00

  • The Fischer 344/NNiaHSd X Brown Norway/BiNia is a better model of sarcopenia than the Fischer 344/NNiaHSd: a comparative analysis of muscle mass and contractile properties in aging male rat models.

    abstract::Sarcopenia, characterized by profound muscle atrophy and the loss of contractile function, contributes significantly to the development of frailty and functional impairment in older age. Although present in aging humans, rat models have failed to clearly demonstrate a similar degree of this age-associated loss of musc...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-005-4808-0

    authors: Rice KM,Linderman JK,Kinnard RS,Blough ER

    更新日期:2005-01-01 00:00:00

  • A 2D analysis of correlations between the parameters of the Gompertz-Makeham model (or law?) of relationships between aging, mortality, and longevity.

    abstract::When mortality (μ), aging rate (γ) and age (t) are treated according to the Gompertz model μ(t) = μ0eγt (GM), any mean age corresponds to a manifold of paired reciprocally changing μ0 and γ. Therefore, any noisiness of data used to derive GM parameters makes them negatively correlated. Besides this artifactual factor ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-019-09828-z

    authors: Golubev A

    更新日期:2019-12-01 00:00:00

  • Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway.

    abstract::The phytochemical epigallocatechin gallate (EGCG) has been reported to alleviate age-associated immune disorders and organ dysfunction. However, information regarding the mechanistic role of EGCG in the suppression of cellular senescence is limited. The present study thus assessed the effects and underlying mechanisms...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-018-9785-1

    authors: Kumar R,Sharma A,Kumari A,Gulati A,Padwad Y,Sharma R

    更新日期:2019-04-01 00:00:00

  • Gene expression hallmarks of cellular ageing.

    abstract::Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age-l...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1007/s10522-018-9750-z

    authors: Frenk S,Houseley J

    更新日期:2018-12-01 00:00:00

  • Daily chronomics of proteomic profile in aging and rotenone-induced Parkinson's disease model in male Wistar rat and its modulation by melatonin.

    abstract::Aging is associated with changes in several basic parameters of circadian timing system (CTS) in mammals leading to circadian dysfunction. We had reported earlier that upon aging and in rotenone induced Parkinson's disease (RIPD) rat model there were significant alterations in the core clock genes expression levels an...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-017-9711-y

    authors: Jagota A,Mattam U

    更新日期:2017-08-01 00:00:00

  • Reproduction and survival in Mediterranean fruit flies: a "protein and energy" free radical model of aging.

    abstract::We propose a "protein and energy" free radical model of aging that predicts patterns of survival and fertility curves for Mediterranean fruit flies. Mathematical and simulation models of individual physiological processes were constructed in terms of stochastic differential equations. The free radical theory of aging ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1023/B:BGEN.0000006559.59110.10

    authors: Butov AA,Carey JR,Volkov MA,Sehl ME,Yashin AI

    更新日期:2003-01-01 00:00:00

  • Chronic treatment with low doses of estradiol affects pituitary and thyroid function in young and middle-aged ovariectomized rats.

    abstract::Menopause marks the end of the reproductive life span of women and is characterized by a dramatic drop of circulating estrogen. Hormone replacement therapy (HRT) has been successfully used to treat the symptoms of menopause because estrogen has strong suppressive effects on climacteric complaints. As the hypothalamo-p...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-005-2623-2

    authors: Böttner M,Wuttke W

    更新日期:2005-01-01 00:00:00

  • Age-specificity and the evolution of senescence: a discussion.

    abstract::Senescence evolved because selection pressure declines with age. However, to explain senescence it does not suffice to demonstrate that selection pressure declines. It is also necessary to postulate biological mechanisms that lead to a deteriorated state of the organism at high ages, but not before. This has lead to t...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-012-9410-7

    authors: Wensink M

    更新日期:2013-02-01 00:00:00

  • Effect of insulin and growth hormone on rat heart and liver oxidative stress in control and caloric restricted animals.

    abstract::In order to know if insulin-like signalling is involved in the control of oxidative stress in mammalian tissues in relation to aging, ad libitum-fed and caloric restricted Wistar rats were treated during 2 weeks with GH and insulin. The most consistent effect of the hormonal treatments was an increase in plasma IGF-1 ...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-004-7380-0

    authors: Sanz A,Gredilla R,Pamplona R,Portero-Otín M,Vara E,Tresguerres JA,Barja G

    更新日期:2005-01-01 00:00:00

  • Bridging the gap between the laboratory and the clinic for patients with sarcopenia.

    abstract::Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major public health issue. Sarcopenia is associated with an increased risk of falls, disability, dependency, institutionalization, hospital stay and early death. Finding interventions to stabilize, reverse or prevent sarcopenia is therefore a ke...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-018-09793-z

    authors: Witham MD

    更新日期:2019-04-01 00:00:00

  • Hutchinson-Gilford progeria syndrome as a model for vascular aging.

    abstract::Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a de novo genetic mutation that leads to the accumulation of a splicing isoform of lamin A termed progerin. Progerin expression alters the organization of the nuclear lamina and chromatin. The life expectancy of HGPS patients is severe...

    journal_title:Biogerontology

    pub_type: 杂志文章,评审

    doi:10.1007/s10522-015-9602-z

    authors: Brassard JA,Fekete N,Garnier A,Hoesli CA

    更新日期:2016-02-01 00:00:00

  • Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria.

    abstract::It is known that a global decrease in food ingestion (dietary restriction, DR) lowers mitochondrial ROS generation (mitROS) and oxidative stress in young immature rats. This seems to be caused by the decreased methionine ingestion of DR animals. This is interesting since isocaloric methionine restriction in the diet (...

    journal_title:Biogerontology

    pub_type: 杂志文章

    doi:10.1007/s10522-012-9384-5

    authors: Sanchez-Roman I,Gómez A,Pérez I,Sanchez C,Suarez H,Naudí A,Jové M,Lopez-Torres M,Pamplona R,Barja G

    更新日期:2012-08-01 00:00:00