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{
"question": [
"List as many studies as you can that include rapamycin.",
"Why is it so diffuclut to map gene loci that control aging in humans?",
"What is apoptosis?",
"which genes are involved in the aging process",
"what causes the aging process",
"which genes are involved in aging",
"what genes are involved in the aging process",
"Describe the genotypes related to Alzheimers and dementia which have commonalities with those for aging.",
"Describe the genotypes related to Alzheimer's and dementia which have commonalities with those for aging.",
"What genetic factors influence aging in humans?",
"what genes are associated with aging?",
"Which genes are associated with aging in human",
"What is GeneNetwork and how does it relate to aging research?"
],
"answer": [
"Here are the studies that include rapamycin: 1. **Yin L, Ye S, Chen Z, Zeng Y (2012)**: \"Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice\" [1]. 2. **Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010)**: \"Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease\" [1]. 3. **Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV, Blagosklonny MV (2011)**: \"Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice\" [2]. 4. **Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. (2012)**: \"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity\" [5]. 5. **Tataranni T, Biondi G, Cariello M, Mangino M, Colucci G, Rutigliano M, et al. (2011)**: \"Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and klotho expression\" [5]. 6. **Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, et al. (2012)**: \"Rapamycin slows aging in mice\" [7]. 7. **Reihl K, Seals D, Henson G, LaRocca T, Magerko K, Bosshardt G, et al. (2013)**: \"Dietary rapamycin selectively improves arterial function in old mice\" [7]. 8. **Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, et al. (2014)**: \"Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction\" [10]. These references provide a comprehensive list of studies involving rapamycin.",
"Mapping gene loci that control aging in humans is difficult due to several reasons: 1. **Complexity of the Phenotype**: Aging is a highly complex phenotype influenced by numerous genes and their interactions with environmental factors. This complexity makes it challenging to identify specific genetic loci that control aging [10]. 2. **Multiple Pathophysiological Processes**: Multiple genes could mediate the aging process through various pathophysiological processes and diseases, adding layers of complexity to the genetic mapping [6]. 3. **Rare vs. Common Variants**: Finding common genetic variants that account for the entire genetic component of human lifespan variability has proven difficult. If rare variants explain most of the genetic variation in aging, new genotyping techniques and analysis methods are required to identify these genes and pathways [3], [4]. 4. **High Number of Loci**: There are more than 1000 loci that exhibit age-dependent changes in gene expression. Not all of these loci are causally involved in aging, making it a substantial challenge to sort out which ones are relevant [8]. 5. **Species Differences**: Many loci that control aging in model organisms like Drosophila may not have the same effect on human aging. This lack of direct correlation between species complicates the identification of relevant human aging genes [1]. 6. **Heritability and Genetic Variation**: While some fraction of human lifespan is heritable, the genetic variation contributing to aging is complex and involves numerous loci associated with age-related traits, further complicating the mapping process [7]. These factors collectively contribute to the difficulty in mapping gene loci that control aging in humans.",
"Apoptosis is a form of programmed cell death that is essential for normal cell turnover and various biological processes [1]. It is characterized by a sequence of well-defined events leading to cell destruction [2]. Apoptosis occurs in a controlled manner, resulting in the elimination of cells by macrophages without causing secondary damage to surrounding cells [3]. This process can be initiated through several pathways, including Bcl-2 activation of caspases, signals from death receptors on the plasma membrane, or induction by granzyme B secreted from cytotoxic T cells [1].",
"Several genes are involved in the aging process, as identified in the provided context: 1. **APOE**: This gene is involved in lipoprotein metabolism and is one of the candidate genes related to longevity [2]. 2. **Genes involved in cell cycle regulation, cell growth, and signal transduction**: These genes play a role in maintaining genome stability and are implicated in the aging process [2]. 3. **Genes involved in DNA repair and chromatin remodeling**: These genes are down-regulated during aging, indicating their involvement in the aging process [3], [7]. 4. **Genes inducing apoptosis**: These genes are also associated with the aging process [4]. 5. **Werners syndrome gene**: Mutations in this gene result in segmental progeroid syndromes, which are related to aging [5]. 6. **Genes in the insulin/insulin-like signaling pathway**: These genes are critical in pathways previously related to aging [5]. 7. **Genes driving cellular senescence**: These genes tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes [6]. These genes collectively contribute to various aspects of the aging process, including genomic stability, cellular senescence, and response to oxidative stress.",
"The aging process is caused by several factors, including: 1. **Accumulated Damage**: Age-related decline results from damaging by-products of metabolism and/or inefficient repair mechanisms, leading to damage that accumulates throughout the lifespan [2]. 2. **Mutation Accumulation**: A process of mutation accumulation in somatic cells, although no specific mechanism has been proposed for how this leads to the multitude of degenerative processes that comprise aging [3]. 3. **Free Radicals and Oxidative Stress**: The theory of free radicals suggests that aging results from inadequate protection against cell and tissue damage by free radicals and oxidative stress throughout life [4]. 4. **Wear-and-Tear**: The wear-and-tear theory posits that cumulative damage from the continuous functioning of vital processes leads to aging and death due to stochastic errors gradually arising [4]. 5. **Cell Senescence and Death Pathways**: Cell senescence and cell death pathways are major causes of aging phenotypes, such as organ atrophy, which appear to be pre-programmed responses of a sizable fraction of the cell population [6]. 6. **Accumulated Defects in Function**: Progressive changes in a cell or organism lead to accumulated defects in function, resulting in system failure and death [8]. 7. **Loss of Genomic Stability**: Loss of genomic stability due to reduced DNA repair capacities, loss of proliferative potential caused by increased senescence, and age-related alterations in DNA-methylation patterns that affect cellular plasticity [9]. These factors collectively contribute to the aging process and the associated decline in physiological functions.",
"Several genes are involved in the aging process, as identified in various studies: 1. **APOE**: This gene is involved in lipoprotein metabolism and is critically related to longevity [4]. 2. **Superoxide dismutase**: A free-radical scavenger gene that has been shown to increase lifespan in model organisms [8]. 3. **Methuselah**: A potential G protein-coupled receptor gene in *Drosophila melanogaster* associated with increased lifespan [8]. 4. **p66shc**: An oxidative stress-response gene involved in aging [8]. 5. **Insulin/IGF1/GH pathway genes**: These genes are part of a pathway that affects longevity across different model organisms [5]. 6. **Genes involved in DNA repair and chromatin remodeling**: These genes are down-regulated during aging [7]. 7. **Genes associated with cellular senescence**: These include genes that induce or inhibit cellular senescence, which are overexpressed with age and are linked to anti-longevity and tumor-suppressor functions [2]. Additionally, studies have identified between 300 to 750 genes related to longevity that are involved in various life activities such as growth, development, energy metabolism, oxidative stress, genomic stability maintenance, and neurocognition [4].",
"Several genes are involved in the aging process, each playing a role in various biological activities and pathways. Key genes and their associated functions include: 1. **APOE**: Involved in lipoprotein metabolism [2]. 2. **Superoxide dismutase**: A free-radical scavenger [8]. 3. **Methuselah**: A potential G protein-coupled receptor in *Drosophila melanogaster* [8]. 4. **p66shc**: An oxidative stress-response gene [8]. 5. **Genes involved in DNA repair and chromatin remodeling**: These genes are down-regulated during aging [3], [10]. 6. **Genes involved in cell cycle regulation, cell growth, and signal transduction**: These genes help maintain genome stability [2]. 7. **Genes involved in inducing apoptosis**: These genes are associated with damage response [5]. 8. **Genes in the insulin/insulin-like signaling pathway**: Critical in pathways previously related to aging [4]. These genes collectively contribute to processes such as growth and development, energy metabolism, oxidative stress response, genomic stability maintenance, and neurocognition [2].",
"The genotypes related to Alzheimer's disease (AD) and dementia that have commonalities with those for aging include several key genetic factors: 1. **Amyloid Precursor Protein (APP)**: Mutations in the APP gene are implicated in the early-onset form of Alzheimer's disease. This gene is also associated with the aging process, as the accumulation of amyloid plaques is a hallmark of both AD and age-related cognitive decline [1], [10]. 2. **Presenilin 1 and 2 (PSEN1 and PSEN2)**: These genes are also involved in the early-onset form of AD and are linked to the production of amyloid-beta, a protein that accumulates in the brains of individuals with AD and is also associated with aging [1]. 3. **APOE \u03b54 Allele**: The APOE \u03b54 allele is a well-known genetic risk factor for late-onset Alzheimer's disease. It is also associated with aging, as it influences lipid metabolism and is linked to age-related cognitive decline [2], [4]. 4. **Genetic Variance in Age of Onset**: Twin studies suggest that 37-78% of the variance in the age of onset of Alzheimer's disease can be attributed to additive genetic effects, indicating a significant overlap between the genetic factors influencing AD and those affecting the aging process [2]. These genotypes highlight the genetic commonalities between Alzheimer's disease, dementia, and the aging process, emphasizing the multifactorial nature of these conditions.",
"The genotypes related to Alzheimer's disease (AD) and dementia that have commonalities with those for aging include several key genetic factors: 1. **Apolipoprotein E (APOE)**: The APOE gene, particularly the APOE \u03b54 allele, is a well-known genetic risk factor for late-onset Alzheimer's disease. It is also associated with cognitive decline in aging populations [9]. Studies have shown that individuals carrying the APOE \u03b54 allele have an increased risk of developing Alzheimer's disease and exhibit more rapid cognitive decline as they age [8]. 2. **Amyloid Precursor Protein (APP)**: Mutations in the APP gene are implicated in the early-onset form of Alzheimer's disease. While these mutations are rare, they contribute to the understanding of the disease's pathology, which overlaps with mechanisms involved in aging, such as amyloid plaque formation [3], [6]. 3. **Presenilin 1 and 2 (PSEN1 and PSEN2)**: Mutations in these genes are also associated with early-onset Alzheimer's disease. These mutations affect the production of amyloid-beta, a key component of the plaques found in the brains of Alzheimer's patients. The accumulation of amyloid-beta is a process that is also observed in the aging brain, albeit to a lesser extent in cognitively healthy individuals [3], [6]. 4. **Genetic Variance in Age of Onset**: Twin studies suggest that a significant portion of the variance in the age of onset of Alzheimer's disease can be attributed to genetic factors, indicating a genetic overlap between aging and the development of Alzheimer's disease [1]. 5. **Vascular Health and Aging**: Vascular health is another important factor that links aging with Alzheimer's disease. Midlife vascular risk factors, such as hypertension and diabetes, are associated with increased amyloid deposition in the brain, which is a hallmark of Alzheimer's disease. This suggests that the genetic factors influencing vascular health and aging may also play a role in the development of Alzheimer's disease [5]. In summary, the genotypes related to Alzheimer's disease and dementia that share commonalities with those for aging include APOE, APP, PSEN1, and PSEN2, as well as genetic factors influencing vascular health and the age of onset of the disease [1], [3], [5], [6], [8], [9].",
"Genetic factors play a significant role in influencing aging in humans. Here are some key points based on the provided context: 1. **Heritability of Longevity**: Human longevity shows a relatively modest heritability of less than 50% [1]. Twin studies have estimated the genetic contribution to general human longevity to be about 20-30% [10]. 2. **Genome-Wide Association Studies (GWAS)**: Large-scale GWAS have identified numerous loci associated with age-related traits, indicating that specific genetic variations can influence aging [7]. 3. **Specific Genetic Variants**: The APOE gene and its variants have been comprehensively analyzed for their association with late-onset Alzheimer's disease, which is an age-related condition [2]. This suggests that certain genetic markers are linked to age-related diseases. 4. **Epigenetic Regulation**: Epigenetic mechanisms, which involve changes in gene expression without altering the DNA sequence, also play a crucial role in aging. Environmental inputs can affect genomic stability through epigenetic regulation [4]. 5. **Inheritance Studies**: Studies on the inheritance of human longevity, such as those conducted in Iceland, have provided insights into the genetic factors that contribute to a longer lifespan [5]. In summary, aging in humans is influenced by a combination of genetic factors, including specific genetic variants, heritability, and epigenetic regulation [1], [2], [4], [5], [7], [10].",
"Several genes have been associated with aging. Here are some key points from the provided context: 1. **Genes in Model Organisms**: A list of genes strongly associated with aging in model organisms includes those involved in segmental progeroid syndromes, such as the Werner syndrome gene, and genes critical in pathways previously related to aging, such as the insulin/insulin-like signaling pathway [1]. 2. **Gene Expression Analysis**: Studies have identified genes overexpressed with age that have protective functions, suggesting they help manage aging and could be targets for manipulation. Gene expression analysis of caloric restriction (CR) has also been conducted to identify associated genes [2]. 3. **Human Longevity-Associated Genes**: Dozens of genes have been associated with human longevity, although only a handful have shown consistent effects across populations [4]. 4. **GenAge Data Set**: A curated list of human genes associated with aging in different model systems is available from the GenAge data set [6]. 5. **GenAge Online Database**: Genes with established aging-related functions were identified by interrogation of the GenAge online database, aging-associated Gene Ontology groups, and hand annotation [9]. These references collectively highlight the involvement of various genes and pathways in the aging process.",
"Several genes have been associated with aging in humans according to the provided context: 1. **GenAge Data Set**: This data set includes genes that may regulate aging in humans or are considerably associated with the human aging phenotype [2]. 2. **HECW2, HIP1, BIN2, GRIA1, KCNQ4, LMO4**: These genes are highly expressed in the brain and have been previously related to the regulation of neuronal excitability and plasticity [4]. 3. **Werners Syndrome Gene**: Mutations in this gene result in segmental progeroid syndromes, which are critical in pathways previously related to aging, such as the insulin/insulin-like signaling pathway [7]. These references indicate that there are multiple genes associated with aging in humans, with some being highly expressed in specific tissues like the brain and others being involved in critical aging-related pathways.",
"GeneNetwork is a resource that has been significantly updated and enhanced to include data from 10 species, multi-omics analysis, updated code, and new tools. It serves as an exciting resource for predictive medicine and systems genetics, constantly being maintained and improved [4]. In relation to aging research, GeneNetwork is used to study genetic networks and pathways linked with aging. For example, researchers use GeneNetwork to construct modular networks of aging, which can provide insights into how different genes interact and affect longevity and aging processes [1]. This network-based approach allows for the identification of potential longevity genes and the links between genes and aging-related diseases [3]. Thus, GeneNetwork plays a crucial role in the functional genomics of aging by enabling the analysis and visualization of complex genetic interactions and their implications for aging and longevity."
],
"contexts": [
[
"168. Yin L, Ye S, Chen Z, Zeng Y . Rapamycin preconditioning attenuates tran- sient focal cerebral ischemia/reperfusion injury in mice. Int J Neurosci. 2012;122:748756. doi: 10.3109/00207454.2012.721827 169. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V . Inhibition of mTOR by rapamy-cin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimers disease. PLoS One. 2010;5:e9979. doi: 10.1371/journal.pone.0009979",
"Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Rosenfeld SV,Blagosklonny MV (2011b) Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 10:42304236 Augustine JJ, Bodziak KA, Hricik DE (2007) Use of sirolimus in solid organ transplantation. Drugs 67:369391 Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP,",
"ACCEPTED MANUSCRIPTACCEPTED MANUSCRIPT mTOR complex 2 (mTORC2), the less clearly identified and less sensitive to rapamycin. Most information to date on the r ole of mTOR has studied the insulin/nutrient signaling via the mTORC1 and significantly less in known about the role of mTORC2 ( in this review, future references measure either mTORC1 or general mTOR activity )[251]. Earlier this decade studies showed that decreasing TOR signaling, genetically or with rapamycin,",
"Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K.,Nadon, N.L., Wilkinson, J.E., Frenkel, K., Carter, C.S., et al. (2009). Rapamycin Cell148, January 20, 2012 2012 Elsevier Inc. 55",
"96. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, etal. Rapamycin- induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335:163843. 97. Tataranni T, Biondi G, Cariello M, Mangino M, Colucci G, Rutigliano M, etal. Rapamycin- induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and klotho expression. Am J Transplant. 2011;11(8):165664.",
"ing these aspects in future studies on the effects of resveratrol could help to study in greater depth the mechanisms of action of this compound [56]. Rapamycin Rapamycin is a macrolide isolated from Streptomyces hygroscopicus, a bacteria from Pascua Island (Rapa Nui). It has functions as an antibiotic, an immune sup- pressant drug, and it is also proposed as a CRM.After the first studies, it was found that rapamycin could induce the extension of the replicative life of yeast through the",
"[257] Wilkinson JE, Burmeister L, Brooks SV, Chan CC, Friedline S, Harrison DE, et al. Rapamycin slows aging in mi ce. Aging Cell. 2012;11:675 -82. [258] Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326:140 -4. [259] Reihl K, Seals D, Henson G, LaRocca T, Mag erko K, Bosshardt G, et al. Dietary rapamycin selectively improves arterial function in old mice. FASEB Journal. 2013;27:1194.17.",
"29. Wilkinson JE, Burmeister L, Brooks SV, Chan C-C, Friedline S, Harrison DE, et al. Rapamycin slows aging in mice. Aging Cell. 2012;11:675 82. 30. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335:1638 43. 31. Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Brkle A, Caiafa P. Reconfiguration of DNA methylation in aging. Mech Ageing Dev. 2015;151:60 70.",
"files [55, 62]. Of note, rapamycin in particular appears to induce additional changes u nrelated to age-associated changes. While both CR and rapamycin induced these non-age-related effects, this effect was much more marked for rapamycin. These non age-related epigenetic changes include gains of methylation at genes, enhancers and CpG islands and losses of methylation at genes and enhancers. Conceivably, such non age-related effects of rapamycin in",
"23 94. Chakrabarti P, English T, Shi J, Smas CM, Kandror KV .Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes. 2010;59:77581. 95. Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, et al. Rapamycin- mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13:46877."
],
[
"that is differentiated at hundreds of loci. Many ofthe loci that control aging in Drosophila will not have the same effect on human aging. On the other hand,we expect that other loci will work in a parallelmanner in humans. We have no way of knowing a priori which group any particular locus will belong in. Thus, the individual mutants that increase Drosophila lifespan may or may not come from loci",
"effect fundamental mechanisms of aging (14, 16). The drawbacksof such studies include the improbability of picking the right geneto study the myriad of known and unknown genes affecting theprocess of interest (17). The linkage study described heremarkedly improves the efficiency of such association studies bydefining a region likely to contain polymorphism(s) with signif-icant influence on life span. Additional association studies with these families and repli-",
"understanding of molecular mechanisms underlyingthe human ageing process. Like other complexhuman traits, nding common variants that accountfor the entire genetic component of human lifespan variability has proved difcult. If rare variants rather than common variants explain most of the genetic vari-ation in ageing among humans, new genotypingtechniques and new analysis methods must be devel-oped to nd genes and pathways involved in ageing.Next-generation sequencing technologies are faster",
"understanding of molecular mechanisms underlyingthe human ageing process. Like other complexhuman traits, nding common variants that accountfor the entire genetic component of human lifespan variability has proved difcult. If rare variants rather than common variants explain most of the genetic vari-ation in ageing among humans, new genotypingtechniques and new analysis methods must be devel-oped to nd genes and pathways involved in ageing.Next-generation sequencing technologies are faster",
"Map contains 1119 and 1459 curated human and mouse aginggenes, respectively, covering almost all scales of aging, rangingfrom molecular damage to genetic predisposition. Cross-speciescomparison revealed a modest overlap between known humanand mouse aging genes, suggesting both conservation of core sen- escence pathways and fundamental differences in aging between mice and humans (Fig. 2E). Aging-associated genes can alternatively be identified in a",
"Several explanations are possible for the lack of genome- wide signicant ndings. First, mortality is arguably 1 ofthe most complex phenotypes, and several trajectories to-ward extreme old age have been identied (Evert et al.,2003). Multiple genes could mediate the aging process butwould have their effects through numerous different patho-physiological processes and diseases that act as intermediate",
"discover core mechanisms of regulation.ANALYSIS OF HUMAN VARIATION IN THE GENETIC CONTROL OF LONGEVITY Heritability studies have convincingly demonstrated that at least some fraction of human lifespan is heritable. In tandem, large-scale genome-wide association studies (GWAS) have identied numerous loci associated with age-related traits (Buniello et al., 2019). While genetic studies have functionally shown an inverse eect of multiple age-related, disease-",
"[12]More than 1000 loci exhibit age-dependent changes in geneexpression (1264 genes). This is a substantialproblem, because not all of these loci will be causally involved in aging, and there are so many to sort out. An additional application of gene chip technologyis to compare ies with and without a lifespanmodulating physiological treatment. Pletcher et al.",
"such alleles. The frequency of genetic variants wastypically compared between highly aged cases andyoung controls, revealing loci at which genetic variantsmay contribute to a higher or lower probability ofsurvival into old age. So far, this approach hasmainly been applied to study single candidate genessuch as the mammalian orthologues of loci in IIS sig-nalling pathways that emerged from lifespan extensionstudies in animal models. An interesting observationthat needs to be taken into human studies is the",
"Kenyon, 2010; Vellai et al., 2003 ). However, in humans, common variants within genes involved in these pathways have not been consistently associated with lifespan ( Chris-tensen et al., 2006; Kenyon, 2010; Kuningas et al., 2008; Vijg and Suh, 2005 ). The lack of success in the identication of genes related to aging in humans may be due to the complexity of the phenotype. One approach to investigate aging and longevity is to compare frequencies of genetic variants between no-"
],
[
"Cell Death A form of programmed cell death, apoptosis is necessary for normal cell turnover and is essential to a plethora of other biological processes. Apoptosis can be executed via Bcl-2 activation of caspases, via signals from the death receptor on the plasma membrane, or via induction by granzyme Bsecreted from cytotoxic T cells (Tc cells) [ 35]. Endonucleases and proteases are activated by active caspases, eventually leading to the death of the cell. With age, however, apoptotic activity changes.",
"(during development and for maintenance of homeostasis) in multi -cellular organism is apoptosis, which is character ized by a sequence of well -defined events resulting in cell destruction. Dysregulation of apoptosis is responsible for many physiological health problems and diseases; therefore, it is necessary to understand the responsible signaling pathways and complex interplay of cellularprocesses. Results: A combined mathematical model of apoptosis",
"is, apoptosis and necrosis. Apoptosis is considered as thedefault pathway, where cell death occurs in a controlledmanner resulting in the elimination of cells by macrophageswithout secondary damage of the surrounding cells. In con-trast, necrosis is considered an uncontrolled process whichleads to disruption of cells promoting tissue inammation[187]. Several transition states between the two pathways",
"tion of cells undergoing apoptosis. Immunol Today 14: 131 136. 82. Platt N, Silva RP, da Gordon S (1998) Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol 8: 365 372. 83. Giles KM, Hart SP, Haslett C, Rossi AG, Dransfield I (2000) An appetite for apoptotic cells? Controversies and challenges. Br J Haematol 109: 1 12.",
"tion of cells undergoing apoptosis. Immunol Today 14: 131 136. 82. Platt N, Silva RP, da Gordon S (1998) Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol 8: 365 372. 83. Giles KM, Hart SP, Haslett C, Rossi AG, Dransfield I (2000) An appetite for apoptotic cells? Controversies and challenges. Br J Haematol 109: 1 12.",
"the induc-tion of apoptosis.",
"to cancer , b ut probably not rele v ant to the i ntrinsic aging process i n yeast. Apoptosis Cell suicide, or apoptosis, i s a well-studied biological phenomenon in multicellular or g anisms t hat allo ws specic cells to be remo v e d during t he de v e lopment of com- ple x tissues, o r potentially dangerous damaged cells to be destro yed for t he benetof the w hole o r g anism. T he lack of an apparent e v olutionary benet for s uch a p ro-",
"15Apoptosis is caused by the activation of the caspase cascade, which isinitiated by two signaling routes (stress-induced death and death-domainreceptor-induced death) (Domen 2001). This process can be prevented by anti-apoptotic molecules, such as Bcl-2 (Domen and Weissman 2000). Directevidence for the involvement of apoptosis in HSC number regulation came fromthe findings that overexpression of the anti-apoptotic gene bcl-2 led to increasednumbers of Thy-1.1low, Sca-1+, c-kit+, Lin- cells, a population",
"15Apoptosis is caused by the activation of the caspase cascade, which isinitiated by two signaling routes (stress-induced death and death-domainreceptor-induced death) (Domen 2001). This process can be prevented by anti-apoptotic molecules, such as Bcl-2 (Domen and Weissman 2000). Directevidence for the involvement of apoptosis in HSC number regulation came fromthe findings that overexpression of the anti-apoptotic gene bcl-2 led to increasednumbers of Thy-1.1low, Sca-1+, c-kit+, Lin- cells, a population",
"Apoptosis modulating genesApopotosis or programmed cell death is associated withalterations in cell morphology, particularly the nucleus, withendonucleatytic cleavage of DNA into nucleosomal lengthfragments.Apoptosis may resultfrom withdrawalofgrowth signals.Fas, a transmembrane protein of the nerve growth factor/tumor necrosis factor receptor family signals apoptotic de-ath signals apoptotic death in some cell types. Fas but notbel-2 gene expression is negatively regulated by TSH (Ka-wakami et al., 1996),"
],
[
"OTHER AGING RELATED GENES",
"ation of the process of aging. Studies revealed from 300 to 750 genes related to longev- ity that are critically involved in a variety of life activities, such as growth and developme nt, energy metabolism, oxi- dative stress, genomic stability maintenance, and neurocog- nition [ 4]. These candidate genes include mainly APOE, a gene involved in lipoprotein metabolism [ 5,6]. Others are those involved in cell cycle regulation, cell growth and signal transduction, the maintenance of genome stability,",
"down-regulated during aging were genes involved in DNA repair and chromatin remodelling. 55 While these studies revealed thousands of age-regulated genes, the ultimate causes of these expression perturbations remain unknown. Analyzing age-dependent gene expression changes using multi-dimensional genetical genomics could bring the identification of genes causing the age-induced alterations and thereby future therapeutic intervention strategies one step closer. Adding the dimension of epigenetics",
"dam-age, as well as genes involved in inducing apoptosis (10, 11). Theaging process is also accompanied by changes in the expressionpatterns of a number of genes (1214). How the regulation ofgene expression in aging correlates with that in response tooxidative stress, however, is understood poorly.",
"www.ncbi.nlm.nih.gov/homologene) of genes strongly asso-ciated with aging in model organisms. Also included are genesin which mutations result in segmental progeroid syndromes,such as the Werners syndrome gene, as well as genes criticalin pathways previously related to aging, such as the insulin/insulin-like signalling pathway (de Magalhes et al ., 2005a). The",
"genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build",
"those down-regulated during aging were genes involved in DNA repair and chromatin remodelling (Chambers et al. 2007b ). While these studies revealed thousands of age- regulated genes, the ultimate causes of these expressionperturbations remain unknown. Analyzing age-dependent gene expression changes using multidimensional genetical genomics could bring the identification of genes causingthe age-induced alterations and thereby future therapeutic intervention strategies one step closer.",
"lar signatures of mammalian aging. Some of the genes",
"overexpressed with age seem to be a response to aging,in that they have been previously found to have protec-tive functions (de Magalha es et al., 2009b). As such,these genes may help organisms manage aging andcould be targets for manipulation. Likewise, gene ex-pression analysis of CR has been conducted to identifyassociated genes (Lee et al., 1999, 2000). A number ofmolecular signatures have emerged from such studiesthat could be useful to identify candidate processes andpathways that affect aging,",
"al., 2009; Stanfel et al., 2009). Many of these genesmodulate the response to environmental signals, such asfood availability, and act in signaling pathways that ifunderstood can be targeted (Fig. 1). The genetic regula-tion of aging is therefore an emerging field with multipleapplications in the human nutrition, cosmetic, and phar-maceutical industries. AGING GENES AS TARGETS FOR DRUG DISCOVERY 91"
],
[
"in the aging process.",
"age-related decline results from damaging by-products of metabolism and/or inefficient repairmechanisms (27, 32). According to this view, dam-agewhich can take on many formsaccumu-lates throughout the life span (38). The exponentialincrease in mortality and the functional declinethat characterize aging, however, only begin aftersexual maturity, whether this occurs at age 13, as inhumans, age 5, as in monkeys, or at less than 2months, as in mice. Therefore, one alternative viewis that aging is perhaps",
"of a pro-cess of mutation accumulation in somatic cells. While im-plicated as a general cause of aging, no specic mecha-nism has been proposed as to how mutation accumulationcould ever lead to the multitude of degenerative processesthat comprise aging. We have now demonstrated that alarge variety of mutations accumulate with age at greatlydifferent rates in a tissue-specic manner. More recentlywe have shown that while some organs, such as brain, donot seem to accumulate mutations with age at all,",
"this process between proteins and other macromolecules responsible for ageing, while the theory of free radicals suggests that ageing is the result of inadequate pro- tection against cell and tissue damage by free radicals and oxidative stress through- out life. Finally, the wear-and-tear theory poses that the cumulative damage that eventually leads to ageing and death is, in fact, the result of the continuous function- ing of vital processes, during which stochastic errors gradually arise.",
"Many mechanistic theories of aging argue that",
"cell senescence and cell death pathways, are a major cause of aging pheno-types, such as organ atrophy. This would appear to be a pre-programmed cause of aging, since it is a consistent response of a sizable fraction of the cell population. However, cellular responses to damage are unlikely to be the onlyexplanation for aging, since even very old organisms still appear to have am-ple tissue capacity left to function optimally.",
"function during aging.",
"INTRODUCTION The aging process represents progressive changes in a cell or an organism which culminate in death due to accumulated defects in function leading to system failure [1]. These defe cts result in part from accumulated damage to DNA. Such damage may result www.impactaging.com AGING, January 2009, Vol. 1. No 1 Review",
"that induce complex molecular changes and, in turn, a deterioration of cellular structures and function. These changes are major causes of age-related diseases like cancer or cardiovascular disorders [1, 2]. The main mo- lecular adaptations occurring during aging are loss ofgenomic stability due to reduced DNA repair capacities [3], loss of proliferative potential caused by increased senescence [1, 4], and age-related alterations in the DNA-methylation patterns that affect cellular plasticity",
"cause in turn metabolic and cognitive alterations, resulting in increasing vulnerabil- ity to environmental challenge and a growing risk for disease and death [1]. Since aging comprises the greatest risk factor for a variety of chronic diseases, includ- ing cancer, cardiovascular disorders, and neurodegenerative diseases [2], one of the goals of biomedical research is to decipher the molecular mechanism underlying aging, which in turn might facilitate the development of treatments aimed at delay-"
],
[
"OTHER AGING RELATED GENES",
"genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build",
"lar signatures of mammalian aging. Some of the genes",
"ation of the process of aging. Studies revealed from 300 to 750 genes related to longev- ity that are critically involved in a variety of life activities, such as growth and developme nt, energy metabolism, oxi- dative stress, genomic stability maintenance, and neurocog- nition [ 4]. These candidate genes include mainly APOE, a gene involved in lipoprotein metabolism [ 5,6]. Others are those involved in cell cycle regulation, cell growth and signal transduction, the maintenance of genome stability,",
"genes (http://genomics.senescence.info/genes/), more than700 genes have been identified that regulate lifespan inmodel organisms (de Magalha es et al., 2009a). Many ofthese genes and their associated pathwayssuch as theinsulin/IGF1/GH pathwayhave been shown to affect lon-gevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolu-tionarily conserved and may have potential therapeuticapplications (Baur et al., 2006). For example, evidencesuggests the use of",
"www.ncbi.nlm.nih.gov/homologene) of genes strongly asso-ciated with aging in model organisms. Also included are genesin which mutations result in segmental progeroid syndromes,such as the Werners syndrome gene, as well as genes criticalin pathways previously related to aging, such as the insulin/insulin-like signalling pathway (de Magalhes et al ., 2005a). The",
"down-regulated during aging were genes involved in DNA repair and chromatin remodelling. 55 While these studies revealed thousands of age-regulated genes, the ultimate causes of these expression perturbations remain unknown. Analyzing age-dependent gene expression changes using multi-dimensional genetical genomics could bring the identification of genes causing the age-induced alterations and thereby future therapeutic intervention strategies one step closer. Adding the dimension of epigenetics",
"Aging is a biological process universal to eukaryotic organ- isms, and its underlying mechanisms are under intensive study. Genetic analyses of yeast, nematode, fly, and mouse haveuncovered a number of genes, whether mutated or misexpressed,that would increase the lifespans of these organisms (1). These genes include superoxide dismutase , a free-radical scavenger; methuselah , a potential G protein-coupled receptor, in Drosoph- ila melanogaster ; and p66 shc, an oxidative stress-response gene, in",
"The multifactorial and temporal features of aging can beanalyzed efficiently by genome-wide transcriptional profiling,which has been conducted in various model organisms and hu-mans (Melov and Hubbard 2004). Aging is associated with alter-ations in transcript levels of many genes, including those in-volved in evolutionarily conserved mitochondrial and protea-somal functions (McCarroll et al. 2004), some of which havebeen shown to be directly involved in regulating lifespan in C.",
"5. Jiang CH, Tsien JZ, Schultz PG, Hu Y (2001) The effects of aging on gene expression in the hypothalamus and cortex of mice. Proc Natl Acad Sci U S A 98: 19301934. 6. Lu T, Pan Y, Kao SY, Li C, Kohane I, et al. (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429: 883891. 7. Fraser HB, Khaitovich P, Plotkin JB, Paabo S, Eisen MB (2005) Aging and gene expression in the primate brain. PLoS Biol 3: e274. 8. Zahn JM, Poosala S, Owen AB, Ingram DK, Lustig A, et al. (2007) AGEMAP: a"
],
[
"OTHER AGING RELATED GENES",
"ation of the process of aging. Studies revealed from 300 to 750 genes related to longev- ity that are critically involved in a variety of life activities, such as growth and developme nt, energy metabolism, oxi- dative stress, genomic stability maintenance, and neurocog- nition [ 4]. These candidate genes include mainly APOE, a gene involved in lipoprotein metabolism [ 5,6]. Others are those involved in cell cycle regulation, cell growth and signal transduction, the maintenance of genome stability,",
"down-regulated during aging were genes involved in DNA repair and chromatin remodelling. 55 While these studies revealed thousands of age-regulated genes, the ultimate causes of these expression perturbations remain unknown. Analyzing age-dependent gene expression changes using multi-dimensional genetical genomics could bring the identification of genes causing the age-induced alterations and thereby future therapeutic intervention strategies one step closer. Adding the dimension of epigenetics",
"www.ncbi.nlm.nih.gov/homologene) of genes strongly asso-ciated with aging in model organisms. Also included are genesin which mutations result in segmental progeroid syndromes,such as the Werners syndrome gene, as well as genes criticalin pathways previously related to aging, such as the insulin/insulin-like signalling pathway (de Magalhes et al ., 2005a). The",
"dam-age, as well as genes involved in inducing apoptosis (10, 11). Theaging process is also accompanied by changes in the expressionpatterns of a number of genes (1214). How the regulation ofgene expression in aging correlates with that in response tooxidative stress, however, is understood poorly.",
"overexpressed with age seem to be a response to aging,in that they have been previously found to have protec-tive functions (de Magalha es et al., 2009b). As such,these genes may help organisms manage aging andcould be targets for manipulation. Likewise, gene ex-pression analysis of CR has been conducted to identifyassociated genes (Lee et al., 1999, 2000). A number ofmolecular signatures have emerged from such studiesthat could be useful to identify candidate processes andpathways that affect aging,",
"al., 2009; Stanfel et al., 2009). Many of these genesmodulate the response to environmental signals, such asfood availability, and act in signaling pathways that ifunderstood can be targeted (Fig. 1). The genetic regula-tion of aging is therefore an emerging field with multipleapplications in the human nutrition, cosmetic, and phar-maceutical industries. AGING GENES AS TARGETS FOR DRUG DISCOVERY 91",
"Aging is a biological process universal to eukaryotic organ- isms, and its underlying mechanisms are under intensive study. Genetic analyses of yeast, nematode, fly, and mouse haveuncovered a number of genes, whether mutated or misexpressed,that would increase the lifespans of these organisms (1). These genes include superoxide dismutase , a free-radical scavenger; methuselah , a potential G protein-coupled receptor, in Drosoph- ila melanogaster ; and p66 shc, an oxidative stress-response gene, in",
"nicance of genes that were found to be aected by aging,the most prominent appeared to be involved in processesthat involve cell division, cell death and apoptosis, migra-tion of cells, and dierentiation, all of which are consistentwith changes in the dierent stages of neurogenesis. Thesechanges at the molecular level agree with studies at the cel- lular level that report changes in rate of migration, dieren- tiation and neurogenesis with aging ( Seki & Arai, 1995;",
"those down-regulated during aging were genes involved in DNA repair and chromatin remodelling (Chambers et al. 2007b ). While these studies revealed thousands of age- regulated genes, the ultimate causes of these expressionperturbations remain unknown. Analyzing age-dependent gene expression changes using multidimensional genetical genomics could bring the identification of genes causingthe age-induced alterations and thereby future therapeutic intervention strategies one step closer."
],
[
"Introduction Alzheimers disease (AD), a devastating neurodegen- erative disease, is the most common form of dementiaamong the elderly. Genetically, AD is a complex and multifactorial disease with the possible involvement of multiple genes. The rare early-onset form of the diseaseusually follows an autosomal-dominant inheritance pattern and to date three genes have been identified: amyloid precursor protein ( APP) and presenilin 1 and 2(PSEN1 andPSEN2 ). The common late-onset form of",
"Background Age-related neurological diseases such as stroke and dementia represent a substantial population burden, and one in three persons will develop either stroke or demen- tia in their lifetime [1]. Twin studies suggest that 3778% of the variance in the age of onset of Alzheimer's disease (AD), the most common cause of dementia in the elderly, can be attributed to additive genetic effects [2,3]. Con- versely, cognitively healthy aging also has a substantial",
"cognitive status in Alzheimer's disease. Neurobiol. Aging 1996 , 17: 921-933. [3] Ertekin-Taner, N. Genetics of Alzheimer's disease: a centennial review. Neurol. Clin. 2007 , 25: 611-667. [4] Bernardi, L., Tomaino, C., Anfossi, M., Gallo, M., Geracitano, S., Puccio, G., Colao, R., Frangipane, F., Mirabelli, M., Smirne, N., Giovanni Maletta, R., Bruni, A.C. Late onset familial Alzheimer's disease: novel presen ilin 2 mutation and PS1 E 318G polymor- phism. J. Neurol. 2008 , 255: 604-606.",
"Keywords: alzheimers disease; genomics; GWAS; genetic risk factors; epigenetic modication; aging 1. Introduction Alzheimers disease (AD) is the most common cause of dementia, accounting for approximately 6080% of dementia cases, followed by vascular dementia (approximately 10%), Lewy Body or Parkinsons disease-related dementia, and alcohol-mediated dementia [ 1]. Mild cognitive impairment, one of the representative early symptoms of AD, makes this disease distinguishable from other types",
"14. Heyman A, Wilkinson WE, Hurwitz BJ, Schmechel D, Sigmon AH, et al. (1983) Alzheimers disease: genetic aspects and associated clinical disorders. AnnNeurol 14: 507515. 15. Farrer LA, Myers RH, Connor L, Cupples LA, Growdon JH (1991) Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J HumGenet 48: 10261033. 16. Duara R, Lopez-Alberola RF, Barker WW, Loewenstein DA, Zatinsky M, et al. (1993) A comparison of familial and sporadic Alzheimers disease. Neurology 43: 13771384.",
"(2016). 3. DeTure, M. A. & Dickson, D. W . The neuropathological diagnosis of Alzheimers disease. Mol. Neurodegener. 14, 32 (2019). 4. Gatz, M. et al. Heritability for Alzheimers disease: the study of dementia in Swedish twins. J. Gerontol. A Biol. Sci. Med. Sci. 52, M117M125 (1997). 5. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168174 (2006).",
"Lett 379(3):199204. Avramopoulos D. 2009. Genetics of Alzheimers disease: Recent advances. Genome Med 1(3):34. Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger A, DAgostino RB, White LR. 1992. Prevalence of dementia and probable seniledementia of the Alzheimer type in the Framingham study. Neurology42(1):115119. Barral S, Cheng R, Reitz C, Vardarajan B, Lee J, Kunkle B, Beecham G,",
"[11] and the exclusion of cerebrovascular factors as inherentetiopathogenic determinants of neuronal deathin AD, taking into account that in patients olderthan 70 years of age the vast majority of caseswith dementia show a clear cerebrovascular com-promise [12]. In addition, most studies attempt- ing to correlate clinical features with singlegenotypes are partially biased due to heterogene-ity and inaccuracy in phenotype recruitment.Furthermore, 6080% of the therapeutic fail-ures in AD",
"associated with Alzheimers disease neuropathology. J. Alzheimers Dis. 60, 10351043 (2017). 63. Gottesman, R. F. etal. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 317, 14431450 (2017). 64. Moran, C. etal. T ype 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology 85, 11231130 (2015). 65. Vemuri, P . etal. Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann. Neurol. 82, 706718 (2017).",
"Introduction Alzheimers disease (AD), the most common form of dementia, is highly heritable (heritability of up to 76%) but genetically complex.1Neuropatho- logically, the disease is characterized by extracellular senile plaques containing b-amyloid (A b) and intra- cellular neurofibrillary tangles containing hyperpho-sphorylated tau protein. 1Before 2009, four genes had been definitively implicated in its aetiology. Muta- tions of the amyloid precursor protein (APP) gene"
],
[
"Background Age-related neurological diseases such as stroke and dementia represent a substantial population burden, and one in three persons will develop either stroke or demen- tia in their lifetime [1]. Twin studies suggest that 3778% of the variance in the age of onset of Alzheimer's disease (AD), the most common cause of dementia in the elderly, can be attributed to additive genetic effects [2,3]. Con- versely, cognitively healthy aging also has a substantial",
"cognitive status in Alzheimer's disease. Neurobiol. Aging 1996 , 17: 921-933. [3] Ertekin-Taner, N. Genetics of Alzheimer's disease: a centennial review. Neurol. Clin. 2007 , 25: 611-667. [4] Bernardi, L., Tomaino, C., Anfossi, M., Gallo, M., Geracitano, S., Puccio, G., Colao, R., Frangipane, F., Mirabelli, M., Smirne, N., Giovanni Maletta, R., Bruni, A.C. Late onset familial Alzheimer's disease: novel presen ilin 2 mutation and PS1 E 318G polymor- phism. J. Neurol. 2008 , 255: 604-606.",
"Introduction Alzheimers disease (AD), a devastating neurodegen- erative disease, is the most common form of dementiaamong the elderly. Genetically, AD is a complex and multifactorial disease with the possible involvement of multiple genes. The rare early-onset form of the diseaseusually follows an autosomal-dominant inheritance pattern and to date three genes have been identified: amyloid precursor protein ( APP) and presenilin 1 and 2(PSEN1 andPSEN2 ). The common late-onset form of",
"[11] and the exclusion of cerebrovascular factors as inherentetiopathogenic determinants of neuronal deathin AD, taking into account that in patients olderthan 70 years of age the vast majority of caseswith dementia show a clear cerebrovascular com-promise [12]. In addition, most studies attempt- ing to correlate clinical features with singlegenotypes are partially biased due to heterogene-ity and inaccuracy in phenotype recruitment.Furthermore, 6080% of the therapeutic fail-ures in AD",
"associated with Alzheimers disease neuropathology. J. Alzheimers Dis. 60, 10351043 (2017). 63. Gottesman, R. F. etal. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 317, 14431450 (2017). 64. Moran, C. etal. T ype 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology 85, 11231130 (2015). 65. Vemuri, P . etal. Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann. Neurol. 82, 706718 (2017).",
"Introduction Alzheimers disease (AD), the most common form of dementia, is highly heritable (heritability of up to 76%) but genetically complex.1Neuropatho- logically, the disease is characterized by extracellular senile plaques containing b-amyloid (A b) and intra- cellular neurofibrillary tangles containing hyperpho-sphorylated tau protein. 1Before 2009, four genes had been definitively implicated in its aetiology. Muta- tions of the amyloid precursor protein (APP) gene",
"Keywords: alzheimers disease; genomics; GWAS; genetic risk factors; epigenetic modication; aging 1. Introduction Alzheimers disease (AD) is the most common cause of dementia, accounting for approximately 6080% of dementia cases, followed by vascular dementia (approximately 10%), Lewy Body or Parkinsons disease-related dementia, and alcohol-mediated dementia [ 1]. Mild cognitive impairment, one of the representative early symptoms of AD, makes this disease distinguishable from other types",
"14. Heyman A, Wilkinson WE, Hurwitz BJ, Schmechel D, Sigmon AH, et al. (1983) Alzheimers disease: genetic aspects and associated clinical disorders. AnnNeurol 14: 507515. 15. Farrer LA, Myers RH, Connor L, Cupples LA, Growdon JH (1991) Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J HumGenet 48: 10261033. 16. Duara R, Lopez-Alberola RF, Barker WW, Loewenstein DA, Zatinsky M, et al. (1993) A comparison of familial and sporadic Alzheimers disease. Neurology 43: 13771384.",
"disease. Nat. Genet. ,19, 321 322. 7. Bergem, A.L., Engedal, K. and Kringlen, E. (1997) The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch. Gen. Psychiat. ,54, 264 270. 8. Payami, H., Grimslid, H., Oken, B., Camicioli, R., Sexton, G., Dame, A., Howieson, D. and Kaye, J. (1997) A prospective study of cognitive health inthe elderly (Oregon Brain Aging Study): effects of family history andapolipoprotein E genotype. Am. J. Hum. Genet. ,60, 948 956.",
"Lett 379(3):199204. Avramopoulos D. 2009. Genetics of Alzheimers disease: Recent advances. Genome Med 1(3):34. Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger A, DAgostino RB, White LR. 1992. Prevalence of dementia and probable seniledementia of the Alzheimer type in the Framingham study. Neurology42(1):115119. Barral S, Cheng R, Reitz C, Vardarajan B, Lee J, Kunkle B, Beecham G,"
],
[
"Recent developments on the genetics of aging can be seen as several streams of effort. In general, humans show a relatively modest ( <50%) heritability of",
"effect genetic variants on human longevity. Aging 2, 612620. Yu, C.E., Seltman, H., Peskind, E.R., Galloway, N., Zhou, P.X., Rosenthal, E., Wijsman, E.M., Tsuang, D.W., Devlin, B., Schellenberg, G.D., 2007. Comprehensive analysis of APOE and selected proximate markers for late-onset Alzheimers disease: patterns of linkage disequilibrium and disease/marker association. Genomics",
"It is undisputed that genetic factors influence aging. In a remarkable",
"males: what are the molecular and evolutionary causes? Aging Cell. 2007;6:225233. doi:10.1111/j.1474-9726.2007.00279.x 63. Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: link- ing environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593610. doi:10.1038/nrm4048 64. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell. 2016;166:822839. doi:10.1016/j.cell.2016.07.050",
"Genet 1998, 81:92-97. 3. Pedersen NL, Posner SF, Gatz M: Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins. Am J Med Genet 2001, 105:724-728. 4. Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR, Stefansson K: Inheritance of human longevity in Iceland. Eur J Hum Genet 2000, 8:743-749. 5. Flossmann E, Schulz UG, Rothwell PM: Systematic review of methods and results of studie s of the genetic epidemiology",
"population dynamics on the genetic architecture of human longevity. Aging (Albany NY). 2018;10(8):1947 63. 68. Bellenguez C, Kucukali F, Jansen I, Andrade V, Morenau-Grau S, Amin N, et al. Large meta-analysis of genome-wide association studies expands knowledge of the genetic etiology of Alzheimer disease and highlights potential translational opportunities. medRxiv. 2020. 69. Kojima T, Shimazui T, Hinotsu S, Joraku A, Oikawa T, Kawai K, et al. Decreased expression of CXXC4 promotes a",
"discover core mechanisms of regulation.ANALYSIS OF HUMAN VARIATION IN THE GENETIC CONTROL OF LONGEVITY Heritability studies have convincingly demonstrated that at least some fraction of human lifespan is heritable. In tandem, large-scale genome-wide association studies (GWAS) have identied numerous loci associated with age-related traits (Buniello et al., 2019). While genetic studies have functionally shown an inverse eect of multiple age-related, disease-",
"than in healthy elderly patients [71]. Concluding Remarks The study of the human aging process is complex and multifactorial, where genetic and environmental variables are key players in its development. That is why we sug- gest a series of different biomarkers which include hormonal, inflammatory, and oxidative stress biomarkers. However, it is possible that other biomarkers such as DNA damage, telomere length determination, DNA repair mechanisms and p53",
"Clinical Genetics and Genomics of Aging",
"standing the cause and mechanisms of aging is imperative in assisting to suppress age-related diseases and promote healthylongevity. It is well-known that aging is influenced by a combin- ation of genetic and environmental factors. Previous twin stud- ies have shown that the genetic contribution to general human longevity is about 2030% [ 4,5], whereas environmental factors in human aging and longevity still account for the largest effect. Epigenetic factors influence the regulation of gene expres-"
],
[
"www.ncbi.nlm.nih.gov/homologene) of genes strongly asso-ciated with aging in model organisms. Also included are genesin which mutations result in segmental progeroid syndromes,such as the Werners syndrome gene, as well as genes criticalin pathways previously related to aging, such as the insulin/insulin-like signalling pathway (de Magalhes et al ., 2005a). The",
"overexpressed with age seem to be a response to aging,in that they have been previously found to have protec-tive functions (de Magalha es et al., 2009b). As such,these genes may help organisms manage aging andcould be targets for manipulation. Likewise, gene ex-pression analysis of CR has been conducted to identifyassociated genes (Lee et al., 1999, 2000). A number ofmolecular signatures have emerged from such studiesthat could be useful to identify candidate processes andpathways that affect aging,",
"OTHER AGING RELATED GENES",
"In addition to aging- and CR-related genes, another source of candidate genes and pathways for drug designare human longevity-associated genes (Barzilai andShuldiner, 2001; Browner et al., 2004; Kenyon, 2010).Dozens of genes have now been associated with humanlongevity (de Magalha es et al., 2009a), although only ahandful of genes have been shown to have consistenteffects across populations. Many longevity-associated genes are related to spe-",
"potentially associated with human ageing. For eachgene, a description compiled from the studies that linkthe gene to ageing is provided. It should be noted thatour focus is on genes that might affect the ageingprocess, rather than individual age-related pathologies; genes affecting multiple, even if not all, age-related",
"Pleiotropies and Aging-Related Genesets To study genes that have been previously related to aging, a list of curated human genes associated with aging in different model systems was obtained from the GenAge data set ( de Magalh ~aes et al. 2005 ). We used gene ontology (GO) anno-",
"aging in human muscle reveals a common aging signa-ture. PLoS Genet. 2, e115. ( doi:10.1371/journal.pgen. 0020115 ) 64 Lener, T ., Moll, P . R., Rinnerthaler, M., Bauer, J., Aberger, F. & Richter, K. 2006 Expression proling ofaging in the human skin. Exp. Gerontol. 41, 387397. (doi:10.1016/j.exger.2006.01.012 ) 65 Kim, S. K. 2008 Genome-wide views of aging gene net- works . Molecular Biology of Aging Monograph 9. Cold Spring Harbor, CT: Cold Spring Harbor LaboratoryPress.",
"aging in human muscle reveals a common aging signa-ture. PLoS Genet. 2, e115. ( doi:10.1371/journal.pgen. 0020115 ) 64 Lener, T ., Moll, P . R., Rinnerthaler, M., Bauer, J., Aberger, F. & Richter, K. 2006 Expression proling ofaging in the human skin. Exp. Gerontol. 41, 387397. (doi:10.1016/j.exger.2006.01.012 ) 65 Kim, S. K. 2008 Genome-wide views of aging gene net- works . Molecular Biology of Aging Monograph 9. Cold Spring Harbor, CT: Cold Spring Harbor LaboratoryPress.",
"tive-gerontogenes and genes with established aging-relatedfunctions were identified by interrogation of the GenAgeonline database [12], from aging-associated Gene Ontology( G O ) g r o u p s a n d f r o m h a n d a n n o t a t i o n ( s e e M a t e r i a l s a n dmethods/Results for a detailed description of the analysis). We show that the fundamenta l changes in genes and proc-",
"on model organisms [3] or have been confined to specificaging-associated disorders such as progeria syndromes [4]. A study of postmortem human brain tissue from 30 individuals aged 26 to 106 years [5] showed that approxi- mately 4% of approximately 11,000 genes analyzed show a significant age-related expression change (1.5-fold or more) in individuals aged >40 years. These genes were reported to play central roles in synaptic plasticity, vesi- cular transport, and mitoch ondrial function. Another"
],
[
"In addition to aging- and CR-related genes, another source of candidate genes and pathways for drug designare human longevity-associated genes (Barzilai andShuldiner, 2001; Browner et al., 2004; Kenyon, 2010).Dozens of genes have now been associated with humanlongevity (de Magalha es et al., 2009a), although only ahandful of genes have been shown to have consistenteffects across populations. Many longevity-associated genes are related to spe-",
"GenAge features a data set of genes that may regulate agingin humans or that at least appear to be considerably associated with the human aging phenotype. This data set includes orthologues derived from established databases, mainly In-Paranoid (OBrien et al ., 2005) but also HomoloGene (http://",
"OTHER AGING RELATED GENES",
"processes in human longevity and aging. Ten of the 22 suggestive associations identied in our analyses are in ornear genes that are highly expressed in the brain (HECW2[Rotin and Kumar, 2009], HIP1 [Blanpied et al., 2003], BIN2, GRIA1), were previously related to the regulation of neuronal excitability and plasticity (KCNQ4 [Van Eyken et al., 2006], LMO4 [Joshi et al., 2009; Leuba et al., 2004],",
"genes analyzed for their possible association with human lon-gevity (http://genomics.senescence.info/genes/longevity.html).All longevity association studies in humans we could find by thetime of the latest update were added to this list. These includestudies reporting negative results, which we see as essentialsince many genes display population-specific associations withlongevity. Fig. 1 From the main page of the Human Ageing",
"Pleiotropies and Aging-Related Genesets To study genes that have been previously related to aging, a list of curated human genes associated with aging in different model systems was obtained from the GenAge data set ( de Magalh ~aes et al. 2005 ). We used gene ontology (GO) anno-",
"www.ncbi.nlm.nih.gov/homologene) of genes strongly asso-ciated with aging in model organisms. Also included are genesin which mutations result in segmental progeroid syndromes,such as the Werners syndrome gene, as well as genes criticalin pathways previously related to aging, such as the insulin/insulin-like signalling pathway (de Magalhes et al ., 2005a). The",
"shown that genes associated with aging and/or longevity inmodel organisms are evolutionary conserved in terms of havingmore homologues than predicted by chance (Budovsky et al .,2007, 2008) and exhibiting slower molecular evolution rates (de Magalhes & Church, 2007). Therefore, it is now clear that atleast some genes identified in model organisms may be relevantto human aging. To allow researchers to focus specifically on human aging,",
"aging in human muscle reveals a common aging signa-ture. PLoS Genet. 2, e115. ( doi:10.1371/journal.pgen. 0020115 ) 64 Lener, T ., Moll, P . R., Rinnerthaler, M., Bauer, J., Aberger, F. & Richter, K. 2006 Expression proling ofaging in the human skin. Exp. Gerontol. 41, 387397. (doi:10.1016/j.exger.2006.01.012 ) 65 Kim, S. K. 2008 Genome-wide views of aging gene net- works . Molecular Biology of Aging Monograph 9. Cold Spring Harbor, CT: Cold Spring Harbor LaboratoryPress.",
"aging in human muscle reveals a common aging signa-ture. PLoS Genet. 2, e115. ( doi:10.1371/journal.pgen. 0020115 ) 64 Lener, T ., Moll, P . R., Rinnerthaler, M., Bauer, J., Aberger, F. & Richter, K. 2006 Expression proling ofaging in the human skin. Exp. Gerontol. 41, 387397. (doi:10.1016/j.exger.2006.01.012 ) 65 Kim, S. K. 2008 Genome-wide views of aging gene net- works . Molecular Biology of Aging Monograph 9. Cold Spring Harbor, CT: Cold Spring Harbor LaboratoryPress."
],
[
"the different pathways linked with aging and even study genenetworks. In such works, GenAge is an adequate resource asit provides a framework for the functional genomics of aging.For example, Xue et al . (2007) used GenAge to construct a modular network of aging and obtain insights into aging, including thefact that genes connecting different modules are more likely toaffect longevity and/or aging, an hypothesis the authors validatedexperimentally in worms (Xue et al",
"[111], and for generation of networks based on known gene interactions such as GeneMania [112] and Cytoscape [113], as well as for identifying cross-species orthology relation-ships [114], network-based thinking has been increasingly applied to the study of aging and lifespan [115-118]. Re-cently, the novel computational method of network identifi- cation by regression (NIR) [119] has been used to identify",
"networks can be built using protein interaction and gene co-expression data. A previous paper used protein- protein interactions to build genetic networks identifying potential longevity genes along with links between genes and aging-related diseases [ 30]. Here, we present the network of proteins and genes co-expressed with the CellAge senescence genes. Assaying the networks, we find links between senescence and immune system func- tions and find genes highly connected to CellAge genes",
"GeneNetwork have reinvigorated it, including the addition of data from 10 species, multi -omics analysis, updated code, and new tools. The new GeneNetwork is now an exciting resource for predictive medicine and systems genetics, which is constantly being maintained and improved. Here, we give a brief overview of the process for carrying out some of the most common functions on GeneNetwork, as a gateway to deeper analyses , demonstrating how a small",
"of GenAge involved finding novel genes that may be linked toaging by way of an analysis of proteinprotein interactions. Theprinciple being that proteins not previously thought to berelated to aging which interact with a large number of proteinsdirectly linked to aging might too be involved in aging and arethus promising candidates for future studies (de Magalhes &Toussaint, 2004; Budovsky et al ., 2007). Similar works are made",
"2009, with over 400 genes added in the current update (Ta-ble1), includingmiRNAs for thefirst time. GenAge has proven a valuable resource for ageing re- search, as evidence by many publications. A systems levelanalysis of the GenAge human genes database identified a robust group of ageing-specific network characteristics, re- vealingageinggenesasnetworkhubs( 11).Moreover,inan analysis of genes in the ageing human brain, 54 genes with sustained, consistent expression and 23 genes with DNA",
"a curated database of genes potentiallyassociated with human aging, and a list of genes testedfor their association with human longevity. A myriad ofbiological data and information is included for hundredsof genes, making GenAge a reference for research thatreflects our current understanding of the genetic basis ofaging. GenAge can also serve as a platform for thesystems biology of aging, and tools for the visualizationof proteinprotein interactions are also included. AnAgeis a database of aging in",
"et al ., 2007). In a sense, GenAge offers an overall view of what is presently known about thegenetics of aging in model organisms and in humans that canbe used for numerous studies, including in contemporary functionalgenomics and systems biology methods.Table 2 Criteria used to select entries for inclusion in the GenAge human data set Main reason for selectionNumber of genes Evidence directly linking the gene product to aging in humans 3",
"senescence.info/genes/) is to host high-quality curatedgene-centric information relevant to human ageing.Although initially GenAge was designed to include onlyhuman genes potentially associated with ageing, thedatabase has signicantly grown since, and several newgene sets have been added to it. For example, GenAge includes, since 2008, a list of genes from model organisms based on genetic manipulation experiments (2). Currently, the database is divided into three main",
"information source on the genetics of aging. In particular forthe human data set, a wealth of biological data is provided foreach entry, including relevant information in the context ofbiogerontology (see example below) to an extent that is notavailable in larger, more generic databases like Entrez Gene.Therefore, to learn about the involvement of a given gene inaging, a quick search in GenAge is the best place to start.GenAge features a sophisticated search engine and its user-friendly interface is easy"
]
]
}
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