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PubMed2005

Control of aging and longevity by IGF-I signaling.

Animal models have established the IGF-I signaling pathway as a key modulator of aging in rodents and invertebrates. Considerable evidence suggests that reduced exposure of tissue to IGF-I is associated with an extended lifespan in these species. In humans, IGF-I is linked to various age-related diseases that are limiting factors for youthful longevity. On one hand, reduced IGF-I activity is associated with significant morbidity in adulthood with an increased risk of developing cardiovascular disease, diabetes, osteoporosis and neurodegenerative diseases. On the other hand, elevated IGF-I levels have been linked to cancer risk given the role of IGF in mediating normal and malignant tissue growth. Thus, IGF is clearly involved in modulating disease of aging; however, the mechanism appears to be complex and interdependent on additional modulating factors. It is attractive to hypothesize that maximal human survival depends on tight regulation of the GH-IGF axis and maintenance of optimal IGF-I action in order to prevent morbidities associated with either deficient or excessive state. Specifically, it is possible that lower levels of IGF-I during early adulthood followed by higher levels of IGF-I later in life may be most beneficial for human longevity by addressing age-specific morbidities.

Aging↗
PubMed2006

Do longevity mutants always show trade-offs?

A number of genetic mutations that substantially increase longevity have been discovered in model organisms. Although these long-lived mutants have provided many insights into the factors that affect longevity, the results from such studies should be interpreted with caution. In particular, at least some of these mutations may be poor guides to human medical intervention because they often have deleterious side effects on important biological functions.

Aging↗
PubMed2006

Quantitative trait loci define genes and pathways underlying genetic variation in longevity.

Quantitative trait locus (QTL) mapping provides a means to discover and roughly position regions of the genome that harbor genes responsible for natural variation in a complex trait. QTL mapping has been utilized extensively in the pursuit of genes contributing to longevity, chiefly in two animal models, the nematode Caenorhabditis elegans and the dipteran insect Drosophila melanogaster. Research on both species has demonstrated that a relatively small set of loci accounts for most of their genetic variance in lifespan. QTL mapping complements the discovery of longevity genes by mutagenesis screens, because the two procedures are predicted to unveil overlapping but distinct types of genes. We argue that information gained from animal models, even invertebrates, can greatly facilitate the process of gene identification and testing of homologous genes in humans.

Aging↗
PubMed2006

Targets of DAF-16 involved in Caenorhabditis elegans adult longevity and dauer formation.

The Forkhead Box O transcription factor DAF-16 regulates genes affecting dauer larva formation and adult life span. Expression profiling and genome-wide searches for DAF-16 binding sites in gene regulatory regions have identified thousands of potential DAF-16 targets. Some of these genes have been shown to alter longevity when their expression is attenuated by RNAi treatment. DAF-16 also associates with other transcription factors, allowing combinatorial modulation of gene expression. Although extensive descriptions of the gene network regulated by DAF-16 have been attempted, there remain many gaps in the understanding of how DAF-16 regulates dauer formation and longevity.

Aging↗
PubMed2006

Longevity and the stress response in Drosophila.

The concept that lifespan is a function of the capacity to withstand extrinsic stress is very old. In concordance with this, long-lived individuals often have increased resistance against a variety of stresses throughout life. Genes underlying the stress response may therefore have the ability to affect lifespan. The progress in modern genetic techniques has allowed researchers to test this idea. The general stress response involves the expression of stress proteins, such as chaperones and antioxidative proteins, downregulation of genes involved in energy metabolism and the release of protective substances. Do these same changes in patterns of expression have the ability to mitigate ageing and prolong lifespan? It appears that parts of this response indeed are also associated with extended longevity, whereas some elements are not, due to their high cost or long-term deleterious consequences. Here we briefly review the state of the art of research on ageing and longevity in the model organism Drosophila, with focus on the role of the general stress response. We will conclude by contemplating some of the implications of the findings in this research and will suggest several directions for future research.

Aging↗
PubMed2005

Endogenous longevity, biological deterioration and economic growth.

The identification of the types of bidirectional interactions that take place between longevity and economic growth in the long-run is carried out by means of the integration of human capital accumulation, innovation in medical technology, a health goods sector, and individual decisions on health and longevity in a dynamic general equilibrium set-up. In this context, in which individual agents decide not only on their "quality" of life but also on its "quantity", the mere process of biological deterioration, that is to say, the continuous loss of health goods effectiveness in maintaining a given level of health as individuals age, provides the reason for an additional, and new, engine of growth.

Economics↗
PubMed2005

Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes.

Aging is associated with a reduced ability to cope with physiological challenges. Although the mechanisms underlying age-related alterations in stress tolerance are not well defined, many studies support the validity of the oxidative stress hypothesis, which suggests that lowered functional capacity in aged organisms is the result of an increased generation of reactive oxygen and nitrogen species. Increased production of oxidants in vivo can cause damage to intracellular macromolecules, which can translate into oxidative injury, impaired function and cell death in vulnerable tissues such as the brain. To survive different types of injuries, brain cells have evolved networks of responses, which detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. The heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response, there is now a strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and there is now evidence that it may play a critical role as modulator of cellular stress response in health and disease states. In the present review, we first discuss the role of nutrition in carnitine metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and we also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.

Acetylcarnitine↗
PubMed2004

The paradox of the insulin/IGF-1 signaling pathway in longevity.

Ageing may be controlled by a genetic-hormonal system that may have originated from a very early common ancestor. One of the pathways that has been implicated in ageing is the insulin/insulin-like growth factor (IGF-1) signaling, which is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like flies, nematodes, and mammalians. While disruption of the insulin/IGF-1 receptor in nematodes and flies increases lifespan significantly, mammals with genetic or acquired defects in insulin signaling pathway are at risk for age-related diseases and increased mortality. This contradiction can be explained by the acquisition of more complicated metabolic pathways in mammalians over evolution. Mammals have insulin/IGF-1 receptors in many organs, but their functions are opposite if they are located in the central nervous system or in the periphery; whereas lower species have insulin/IGF-1 receptors signaling mainly through the nervous system. Furthermore, mammalians have different and very specific receptors for insulin and IGF-1, with distinct pathways and diverse functions. Striking evidence suggests that decreased IGF-1 levels and signaling during early development, but not the insulin signaling may modulate longevity in many species. Thus, paradoxical outcomes follow the decrease of insulin and/or IGF-1 signal pathway in invertebrates and in mammals, prolonging life in the former and shortening it in the latter. In this review we focus on the downstream cascade of events in the insulin and IGF-1 signaling to identify specific pathways that are relevant to human longevity.

Animals↗
PubMedDate not supplied

Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell dwarf mouse livers.

The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell dwarf (Pit-1) mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell dwarf mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in dwarf mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell dwarf mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell dwarf mouse.

Animals↗
PubMed2005

The impact of DNA damage, genetic mutation and cellular responses on cancer prevention, longevity and aging: observations in humans and mice.

Over the past 5 years, data collected from the mouse suggest that pathways important for either preventing or resolving DNA damage are longevity assurance mechanisms whose critical overall function is somatic cell maintenance, a necessary part of cancer prevention. These pathways include those that reduce DNA damage levels caused by exogenous sources, replication errors and by-products of cellular respiration. Unresolved DNA damage leads to permanent mutations in the genetic code that may be oncogenic. Therefore, pathways that resolve DNA damage are important anti-cancer mechanisms. As an important line of defense, there are a variety of pathways that repair DNA damage. In addition, there are anti-cancer pathways that respond to DNA damage by either preventing cellular replication or inducing cell death. Genes in these pathways, termed longevity assurance genes (LAG), code for proteins that reduce cancer incidence and as a result assures a sufficiently long health span needed for reproduction. Data from mouse models, many that were originally designed to study cancer, are showing that a potential consequence of DNA damage and responses to DNA damage is aging; these models support the hypothesis that at least some aspects of normal aging are the consequence of anticancer mechanisms designed to deal with damaged DNA.

Animals↗
PubMed2005

Longevity-associated NADH dehydrogenase subunit-2 polymorphism and serum electrolyte levels in middle-aged obese Japanese men.

Mitochondrial DNA 5178 cytosine/adenine polymorphism, which is also called NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with Japanese longevity. This polymorphism is widely associated with blood pressure, serum lipid levels, hematological parameters, intraocular pressure, and serum protein fraction levels. However, there have been no reports on the association between ND2-237 Leu/Met polymorphism and serum electrolyte levels. To investigate this relationship, we performed an association study in 321 healthy middle-aged Japanese men. Crude data showed that serum sodium levels and serum chloride levels were significantly lower in men with ND2-237 Met than in those with ND2-237 Leu (P = 0.021 and 0.003, respectively). Cigarette consumption and body mass index were significantly and positively associated with serum chloride levels (P = 0.002 and 0.008, respectively) and hemoglobin levels were significantly and negatively associated with them (P = 0.007) in ND2-237 Leu genotypic men. In men with ND2-237 Met, only hemoglobin levels were significantly and negatively associated with serum chloride levels (P = 0.025). After adjusting for covariates, only in male obese (body mass index> or =25) subjects, serum sodium and chloride levels remained significantly lower, and serum calcium levels appeared to be significantly higher in ND2-237 Met than in ND2-237 Leu (P = 0.013, <0.001, and 0.046, respectively). Longevity-associated NADH dehydrogenase subunit-2 polymorphism may influence serum electrolyte levels in middle-aged obese Japanese men.

Amino Acid Substitution↗
PubMed2005

Contribution of an affect-associated gene to human longevity: prevalence of the long-allele genotype of the serotonin transporter-linked gene in Japanese centenarians.

Negative affect such as depression and anxiety has been reported to be associated with morbidity and mortality, and polymorphisms of the serotonin transporter (5HTT) gene may be associated with such affect disorders. Hypothesizing that 5HTT gene polymorphisms could influence human longevity via negative affect; we compared the polymorphic variation of the 5HTT gene between 265 Japanese centenarians and control subjects. In addition, we evaluated the relationships between the 5HTT genotype and the physical, cognitive, and biologic status of centenarians, as indicated by the Barthel Index, the Mini-Mental State Examination, and serum albumin concentration, respectively. The frequency of the l/l genotype and the l allele was significantly greater in centenarians than in younger control subjects, particularly women. A significant effect of the 5HTT genotype on serum albumin concentration was observed in both sexes. Although, there was sex optionality, the l allele may carry a longevity advantage possibly through behavioral mechanisms.

Adult↗
PubMed2006

Extended longevity of wild-derived mice is associated with peroxidation-resistant membranes.

Two lines of mice, Idaho (Id) and Majuro (Ma), both derived from wild-trapped progenitors, have previously been shown to have extended lifespans in captivity when compared to a genetically heterogenous laboratory line of mice (DC). We have examined whether membrane fatty composition varies with lifespan within the species Mus musculus in a similar manner to that previously demonstrated between mammal species. Muscle and liver phospholipids from these long-living mice lines have a reduced amount of the highly polyunsaturated omega-3 docosahexaenoic acid compared to the DC mice, and consequently their membranes are less likely to peroxidative damage. The relationship between maximum longevity and membrane peroxidation index is similar for these mice lines as previously observed for mammals in general. It is suggested that peroxidation-resistant membranes may be an important component of extended longevity.

Animals↗
PubMed2006

Allelic variation in the CNDP1 gene and its lack of association with longevity and coronary heart disease.

Carnosine, a cytoprotective dipeptide found at very high concentrations in skeletal muscle, heart and brain, is cleaved in blood by serum carnosinase which is encoded by the CNDP1 gene. We recently found that homozygosity of a 5-leucine variant in the leader peptide of this enzyme protects diabetes mellitus patients against nephropathy. Hypothesising that the same allele could also be associated with longevity or a reduced incidence of cardiovascular problems, we examined the frequency of CNDP1 alleles in German centenarians, patients with premature coronary heart disease, and matched controls. A total of 1382 individuals was investigated. The 5-leucine allele was the most common allele in all groups investigated. There was no difference in allele or genotype frequency between centenarians and their control group, or between cardiovascular patients and their control group. The recently identified functional carnosinase variant therefore does neither contribute to longevity nor protect against coronary heart disease in our probands. In addition to the known trinucleotide repeat alleles in the CNDP1 gene, we detected a rare 8-leucine allele, a rare duplication, p.L13_V15dup, and a more common frameshift deletion, L17fsX20. Homozygosity for L17fsX20, estimated to have a prevalence of approximately 1:20,000, would be expected to cause carnosinaemia, an autosomal recessive trait with uncertain clinical relevance.

Aged↗
PubMed2006

Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans.

A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.

Aging↗
PubMed2004

Preservation of cognitive and functional ability as markers of longevity.

Longevity is a complex biological process for which the phenotypes have not been established. Preservation of cognitive and physical function may be important and preservation of these functions is, in part, inherited. We investigated the relation between rate of change in cognitive and functional abilities in probands and risk of death in their siblings. Probands were classified as showing no decline, slow, medium, or rapid rate of decline, based on the slope of change in cognitive and physical/functional factors over three or more assessments. Siblings of probands who did not decline on measures of memory, visuospatial/cognitive function or ADL skills were approximately half as likely to die as siblings of probands who had the most rapid decline. The reduction in risk of death in siblings of probands who did not decline in was primarily observed among siblings of probands who were older than 75 years, suggesting that genetic influences on life span may be greater at older ages. There was no association between probands' rate of change in language, IADL skills, upper or lower extremity mobility and risk of death in siblings. The results of the present study identify phenotypes associated with preserved cognitive and functional abilities which may serve as markers for longevity.

Activities of Daily Living↗
PubMed2006

Reproduction and longevity: secrets revealed by C. elegans.

What is the relationship between reproduction and longevity? Evolutionary biology suggests that reproduction exacts a cost in somatic maintenance, a cost that reduces longevity. The frequent occurrence of this tradeoff between life span and fecundity, both due to experimental manipulations as well as natural variation, suggest that the mechanism might be conserved during evolution. Until recently, little was known about the mechanistic details of how reproduction might regulate life span. Here we discuss recent advances in our understanding of the regulation of life span by reproductive signaling, focusing on studies using Caenorhabditis elegans.

Aging↗
PubMed2002

Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot-2 (mortalin)/mthsp70/Grp75.

The Caenorhabditis elegans homolog of mortalin/mthsp70/Grp75 (called mot-2 hereafter) was isolated by screening of a nematode cDNA library with mouse mot-2 cDNA. The isolated clone matched to hsp70F of C. elegans. Analysis with two of the antibodies raised against hsp70F revealed that unlike mammalian mot-2, it is heat inducible. Transient induction of hsp70F by heat shock led to a slight (<13%) extension in the C. elegans life span. The transgenic worms that constitutively over-expressed hsp70F predominantly in muscle showed life span extension (approximately 43% for mean and approximately 45% for maximum life span) as compared to the wild-type and green fluorescent protein-transgenic worms. Life span extension of human cells was obtained by over-expression of mot-2 [Kaul et al. (2000) FEBS Lett. 474, 159-164]. Our results show, for the first time, that this member of the hsp70 family governs the longevity of worms and thus there are common pathways that determine mammalian and worm longevity.

Amino Acid Sequence↗