Determinants Of Longevity Research Articles

Honey bee ( Apis mellifera) workers live longer in small than in large colonies

Social insect colonies are highly integrated units that can be regarded in some respects as super-organisms, with colony size and individuals analogous to body size and cells in unitary organisms. In both, unitary organisms and super-organisms, the relation between body/colony size and lifespan of the constituent units (cells/individuals) is important for understanding systemic aging but remains to be explored. Therefore, this study compared the life-history and longevity of individual honey bee workers between a large and a small colony social environment. We found that individuals in large colonies were consistently shorter lived than individuals in small colonies. This experimental effect occurred in both principal life history phases of honey bee workers, the in-hive and the foraging stage, independently of the age of the workers at their transition between the two. Nevertheless, this age of first foraging was a key determinant of worker longevity, in accordance with previous studies. The large colonies raised more brood, built more comb, and foraged at higher rates. Our results do not comply with the idea that social group size has a positive effect on individual longevity. Instead, our findings suggest that large and small colonies follow different demographic growth trajectories, trading off longevity of individuals for overall colony growth. Similarly, multi-cellular organisms might sacrifice maintenance and repair of their individual constituent cells for enhanced metabolic activity and organismal growth, leading to the widely-observed negative correlation between longevity and body size within species.

Dual targeting of the antagonistic pathways mediated by Sirt1 and TXNIP as a putative approach to enhance the efficacy of anti-aging interventions

The organism's ability to regulate oxidative stress and metabolism is well recognized as a major determinant of longevity. While much research interest in this area is directed towards the study of genes that inhibit oxidative stress and/or improve metabolism, contribution to the aging process of genes with antagonistic effects on these two pathways is still less understood. The present study investigated the respective roles of the histone deacetylase Sirt1 and the thioredoxin binding protein TXNIP, two genes with opposite effects on oxidative stress and metabolism, in mediating the action of putative anti-aging interventions. Experiments were carried out in vitro and in vivo to determine the effect of proven, limited calorie availability, and unproven, resveratrol and dehydroepiandrosterone (DHEA), on the expression of Sirt1 and TXNIP. The results indicated that limited calorie availability consistently inhibited TXNIP in cancer and in normal cells including stem cells, however, it only slightly induced Sirt1expression in cancer cells. In contrast, resveratrol had a biphasic effect, and DHEA inhibited the expression of these two genes in a tissue specific manner, both in vitro and in vivo. Whereas all the three approaches tested inhibited TXNIP through the glycolytic pathway, DHEA acted by inhibiting G6PD and resveratrol through the activation of AMPK. In light of previous reports that Sirt1 induces AMPK-mediated signaling pathway, our findings point to the possibility of a negative relationship between Sirt1 and TXNIP that, if validated, can be exploited to improve the efficacy of putative anti-aging interventions.

Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. Surprisingly, data from the longest-living rodent known, naked mole-rats [MRs; mass 35 g; maximum lifespan (MLSP) > 28.3 years], when compared with mice (MLSP 3.5 years) exhibit higher levels of lipid peroxidation, protein carbonylation, and DNA oxidative damage even at a young age. We hypothesize that age-related changes in protein structural stability, oxidation, and degradation are abrogated over the lifespan of the MR. We performed a comprehensive study of oxidation states of protein cysteines [both reversible (sulfenic, disulfide) and indirectly irreversible (sulfinic/sulfonic acids)] in liver from young and old C57BL/6 mice (6 and 28 months) and MRs (2 and >24 years). Furthermore, we compared interspecific differences in urea-induced protein unfolding and ubiquitination and proteasomal activity. Compared with data from young mice, young MRs have 1.6 times as much free protein thiol groups and similar amounts of reversible oxidative damage to cysteine. In addition, they show less urea-induced protein unfolding, less protein ubiquitination, and higher proteasome activity. Mice show a significant age-related increase in cysteine oxidation and higher levels of ubiquitination. In contrast, none of these parameters were significantly altered over 2 decades in MRs. Clearly MRs have markedly attenuated age-related accrual of oxidation damage to thiol groups and age-associated up-regulation of homeostatic proteolytic activity. These pivotal mechanistic interspecies differences may contribute to the divergent aging profiles and strongly implicate maintenance of protein stability and integrity in successful aging.

Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis

Apoptotic myocyte cell death, diastolic dysfunction, and progressive deterioration in left ventricular pump function characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG) transmits danger signals in cardiac muscle cells. The growth factor adapter protein p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here we demonstrate that interventions which attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser36) inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes obtained by enzymatic dissociation were transduced with mutant-36 p66ShcA (mu-36) dominant-negative expression vector and plated in serum-free media containing 5 or 25 mM glucose. At HG, adult rat ventricular myocytes exhibit a marked increase in reactive oxygen species production, upregulation of phospho-Ser36, collapse of mitochondrial transmembrane potential, and increased formation of p66ShcA/cytochrome-c complexes. These indexes of oxidative stress were accompanied by a 40% increase in apoptosis and the upregulation of cleaved caspase-3 and the apoptosis-related proteins p53 and Bax. To test whether p66ShcA functions as a redox-sensitive molecular switch in vivo, we examined the hearts of male Akita diabetic nonobese (C57BL/6J) mice. Western blot analysis detected the upregulation of phospho-Ser36, the translocation of p66ShcA to mitochondria, and the formation of p66ShcA/cytochrome-c complexes. Conversely, the correction of HG by recombinant adeno-associated viral delivery of leptin reversed these alterations. We conclude that p66ShcA is a molecular switch whose redox function is turned on by phospho-Ser36 and turned off by interventions that prevent this modification.

Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination.

Regulation of hormonal, insulin/IGF-1 (Ins/IGF-1) signaling activities, and pathways of the intrinsic generation of reactive oxygen species (ROS) play a role in aging and longevity determination. In this review we discuss the cross-talk between these pathways as mechanisms of signaling that may be important factors in the regulation of aging and longevity. The balance of physiological processes controlling the rate of aging and longevity in several mouse mutants suggests the involvement of cross-talk mechanisms of regulation of the insulin/IGF1 signaling pathway vs. the ROS signaling pathways. In mice, modulation of the Ins/IGF-1 signaling pathways resulting from the Prop1(df), Pit1(dw) and Igf1 receptor mutations exemplify the hormonal pathways associated with aging and longevity determination. These pathways are also targets of the ROS-mediated redox pathways. Similarly, the Klotho and p66(Shc) mutants link regulation of ROS signaling pathways to aging and longevity determination. Both of these models also display altered insulin signaling activity, a characteristic associated with longevity. The Ins/IGF-1 signaling pathway is of particular interest because of its decreased activity due to genetic manipulation vs. its responsiveness to ROS levels.

Shortest-Path Network Analysis Is a Useful Approach toward Identifying Genetic Determinants of Longevity

BackgroundIdentification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders. To date, however, targeted efforts at identifying longevity-associated genes have been limited by a lack of predictive power, and useful algorithms for candidate gene-identification have also been lacking.Methodology/Principal FindingsWe have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein–protein interaction dataset in order to construct a shortest-path longevity network. To validate this network, the replicative aging potential of 88 single-gene deletion strains corresponding to predicted components of the shortest-path longevity network was determined. Here we report that the single-gene deletion strains identified by our shortest-path longevity analysis are significantly enriched for mutations conferring either increased or decreased replicative life span, relative to a randomly selected set of 564 single-gene deletion strains or to the current data set available for the entire haploid deletion collection. Further, we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction.Conclusions/SignificanceThis work demonstrates that shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity and represents the first application of network analysis of aging to be extensively validated in a biological system. The novel longevity genes identified in this study are likely to yield further insight into the molecular mechanisms of aging and age-associated disease.

The p53–p66shc–Manganese Superoxide Dismutase (MnSOD) network: A mitochondrial intrigue to generate reactive oxygen species

Once considered as a mere by-product of respiration, mitochondrial generation of reactive oxygen species (ROS) has recently emerged as a genetically controlled phenomenon, involved in complex intracellular signal transduction cascades that directly regulate cell survival and death in responses to environmental stressors. These cascades are involved in the pathogenesis of several major age-related diseases, such as cancer and neurodegeneration, and also appear to somehow regulate the “normal” ageing process.The present short review summarizes recent discoveries on mitochondrial reactive oxygen species regulation by p53, a tumor suppressor protein and p66shc, a protein implicated in the life-span determination. It also outlines the emerging network whereby these molecules cross-talk with each other and with the mitochondrial antioxidant system, namely MnSOD (SOD2), another life-span determining protein, to regulate oxidative stress in the organelle. This molecular circuit, which comprises two genetic determinants of longevity and a major tumor suppressor gene, also provides a theoretical framework connecting senescence and cancer.

Cumulative Deficits and Physiological Indices as Predictors of Mortality and Long Life

We evaluated the predictive potential for long-term (24-year) survival and longevity (85+ years) of an index of cumulative deficits (DI) and six physiological indices (pulse pressure, diastolic blood pressure, pulse rate, serum cholesterol, blood glucose, and hematocrit) measured in mid- to late life (44-88 years) for participants of the 9th and 14th Framingham Heart Study examinations. For all ages combined, the DI, pulse pressure, and blood glucose are the strongest determinants of both long-term survival and longevity, contributing cumulatively to their explanation. Diastolic blood pressure and hematocrit are less significant determinants of both of these outcomes. The pulse rate is more relevant to survival, whereas serum cholesterol is more relevant to longevity. Only the DI is a significant predictor of longevity and mortality for each 5-year age group ranging from 45 to 85 years. The DI appears to be a more important determinant of long-term risks of death and longevity than are the physiological indices.

Caenorhabditis elegans HCF-1 Functions in Longevity Maintenance as a DAF-16 Regulator

The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.

Endocrine function in naturally long-living small mammals

The complex, highly integrative endocrine system regulates all aspects of somatic maintenance and reproduction and has been widely implicated as an important determinant of longevity in short-lived traditional model organisms of aging research. Genetic or experimental manipulation of hormone profiles in mice has been proven to definitively alter longevity. These hormonally induced lifespan extension mechanisms may not necessarily be relevant to humans and other long-lived organisms that naturally show successful slow aging. Long-lived species may have evolved novel anti-aging defenses germane to naturally retarding the aging process. Here, we examine the available endocrine data associated with the vitamin D, insulin, glucocorticoid and thyroid endocrine systems of naturally long-living small mammals. Generally, long-living rodents and bats maintain tightly regulated lower basal levels of these key pleiotropic hormones than shorter lived rodents. Similarities with genetically manipulated long-lived rodent models of aging suggest that evolutionary well-conserved hormonal mechanisms are integrally involved in lifespan determination.

A unique life history among tetrapods: An annual chameleon living mostly as an egg

The approximately 28,300 species of tetrapods (four-limbed vertebrates) almost exclusively have perennial life spans. Here, we report the discovery of a remarkable annual tetrapod from the arid southwest of Madagascar: the chameleon Furcifer labordi, with a posthatching life span of just 4-5 months. At the start of the active season (November), an age cohort of hatchlings emerges; larger juveniles or adults are not present. These hatchlings grow rapidly, reach sexual maturity in less than 2 months, and reproduce in January-February. After reproduction, senescence appears, and the active season concludes with population-wide adult death. Consequently, during the dry season, the entire population is represented by developing eggs that incubate for 8-9 months before synchronously hatching at the onset of the following rainy season. Remarkably, this chameleon spends more of its short annual life cycle inside the egg than outside of it. Our review of tetrapod longevity (>1,700 species) finds no others with such a short life span. These findings suggest that the notorious rapid death of chameleons in captivity may, for some species, actually represent the natural adult life span. Consequently, a new appraisal may be warranted concerning the viability of chameleon breeding programs, which could have special significance for species of conservation concern. Additionally, because F. labordi is closely related to other perennial species, this chameleon group may prove also to be especially well suited for comparative studies that focus on life history evolution and the ecological, genetic, and/or hormonal determinants of aging, longevity, and senescence.

The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms

Reactive oxygen species (ROS), inevitable byproducts of aerobic metabolism, are known to cause oxidative damage to cells and molecules. This, in turn, is widely accepted as a pivotal determinant of both lifespan and health span. While studies in a wide range of species support the role of ROS in many age-related diseases, its role in aging per se is questioned. Comparative data from a wide range of endotherms offer equivocal support for this theory, with many exceptions and inconclusive findings as to whether or not oxidative stress is either a correlate or a determinant of maximum species lifespan. Available data do not support the premise that metabolic rate and in vivo ROS production are determinants of lifespan, or that superior antioxidant defense contributes to species longevity. Rather, published studies often show either a negative associate or lack of correlation with species longevity. Furthermore, many long-living species such as birds, bats and mole-rats exhibit high levels of oxidative damage even at young ages. Similarly genetic manipulations altering expression of key antioxidants do not necessarily show an impact on lifespan, even though oxidative damage levels may be affected. While it is possible that these multiple exceptions to straightforward predictions of the free radical theory of aging all reflect species-specific, "private" mechanisms of aging, the preponderance of contrary data nevertheless present a challenge to this august theory. Therefore, contrary to accepted dogma, the role of oxidative stress as a determinant of longevity is still open to question.

Mass spectrometric proteome analysis suggests anaerobic shift in metabolism of Dauer larvae of Caenorhabditis elegans

The Dauer larva is a non-feeding alternative larval stage of some nematodes specialized for long-term survival and dispersal. In this study we compared proteome maps obtained from Dauer larvae with those from the corresponding third larval stage (L3) of the feeding life cycle of C. elegans wild-type strain N2. We demonstrate at the protein level that altered metabolism may participate in longevity determination of Dauers. We detected huge amounts of alcohol dehydrogenase (CE12212) and aldehyde dehydrogenase (CE29809) in Dauer animals, indicating highly active fermentative pathways. Inorganic pyrophosphatase (CE05448) that enables to metabolize pyrophosphate as a high-energy source was over-expressed in Dauers. An interesting differentially expressed protein was phosphatidylethanolamine-binding protein (CE38516) that was found in high abundance in samples from Dauer larvae. Protein synthesis may be lowered in Dauer animals by the reduced expression of splicing factor rsp-3 (CE31089) and methionyl-tRNA synthase (CE34219). We observed significantly lower amounts of the pepsin-like aspartyl protease 1 (CE21681) in non-feeding Dauers, which is in agreement with reduced nutrient digestion. Finally, the hypothetical protein R08E5.2 (CE33294) was present in high abundance in L3 animals.

The exceptional longevity of an egg-laying mammal, the short-beaked echidna ( Tachyglossus aculeatus) is associated with peroxidation-resistant membrane composition

The echidna Tachyglossus aculeatus is a monotreme mammal from Australia that is exceptionally long-living. Its documented maximum lifespan of 50 years is 3.7 times that predicted from its body mass. Other exceptionally long-living mammals (naked mole-rats and humans) are known to have peroxidation-resistant membrane composition, raising the question about echidnas. Phospholipids were extracted from skeletal muscle, liver and liver mitochondria of echidnas and fatty acid composition measured. As with other exceptionally long-living mammals, membrane lipids of echidna tissues were found to have a lower content of polyunsaturates and a higher content of monounsaturates than predicted for their body size. The peroxidation index (=peroxidation susceptibility) calculated from this membrane composition was lower-than-expected for their body size, indicating that the cellular membranes of echidnas would be peroxidation-resistant. Additionally when the calculated peroxidation index was plotted against maximum lifespan, the echidna values conformed to the relationship for mammals in general. These findings support the membrane pacemaker theory of aging and emphasise the potential importance of membrane fatty acid composition in aging and in the determination of maximum longevity.

Do Mitochondrial DNA and Metabolic Rate Complement Each Other in Determination of the Mammalian Maximum Longevity?

In animal cells, mitochondria are semiautonomous organelles of virtually "hostile" (bacterial) origin, with their own code and genome (mtDNA). The semiautonomy and restricted resources could result in occasional "conflicts of interests" with other cellular components, in which mitochondria have greater chances to be "the weakest link," thus limiting longevity. Two principal questions are addressed: (1) to what extent the mammalian maximum life span (MLS) is associated with mtDNA base composition? (2) Does mtDNA base composition correlate with another important mitochondria-associated variable-resting metabolic rate (RMR)-and whether they complement each other in determination of MLS? Analysis of 140 mammalian species revealed significant correlations between MLS and the content of the four mtDNA nucleotides, especially noted for GC pairs (r(2) = 0.42; p < 10(-17)). The most remarkable finding of this study is that multivariate stepwise analysis selected only the GC content and RMR, which together explained 77% of variation in MLS (p < 10(-25)). To the authors' knowledge, it is the highest coefficient of MLS determination that has ever been reported for a comparable sample size. Taking into account substantial errors in estimation of MLS and RMR, it could mean that the GC and RMR explain most of the MLS biological variation. Other putative players in MLS determination should have relatively small contribution or their effects should be realized via the same channels. Although further research is clearly warranted, the extraordinary high correlation of mtDNA GC and RMR with MLS suggests a "direct hitting" of the core longevity targets, inferring mitochondria as a primary object for longevity-promoting interventions.

Exceptional Longevity in Men

Prospective data on nongenetic determinants of exceptional longevity are limited, and information on long-lived men and their functional status is particularly sparse. We examined modifiable factors associated with a life span of 90 or more years and late-life function in men. In this prospective cohort study of 2357 healthy men (mean age, 72 years) within the Physicians' Health Study (1981-2006), biological and lifestyle factors and comorbid conditions were assessed by self-report with baseline and annual questionnaires. Mortality and incidence of major diseases were confirmed by medical record review. Late-life function was assessed 16 years after baseline by the Medical Outcomes Study 36-Item Short-Form Health Survey. A total of 970 men (41%) survived to at least age 90 years. Smoking was associated with increased risk of mortality before age 90 years (hazard ratio [HR]; 2.10; 95% confidence interval [CI], 1.75-2.51), and similar associations were observed with diabetes (HR, 1.86; 95% CI, 1.52-2.26), obesity (HR, 1.44; 95% CI, 1.10-1.90), and hypertension (HR, 1.28; 95% CI, 1.15-1.43). Regular exercise was associated with a nearly 30% lower mortality risk (HR, 0.72; 95% CI, 0.62-0.83). The probability of a 90-year life span at age 70 years was 54% in the absence of smoking, diabetes, obesity, hypertension, or sedentary lifestyle. It ranged from 36% to 22% with 2 adverse factors and was negligible (4%) with 5. Compared with nonsurvivors, men with exceptional longevity had a healthier lifestyle (67% vs 53% had <or=1 adverse factor), had a lower incidence of chronic diseases, and were 3 to 5 years older at disease onset. They had better late-life physical function (mean +/- SD score [maximum 100], 73 +/- 23 vs 62 +/- 30; P < .001) and mental well-being (mean score, 84 +/- 14 vs 81 +/- 17; P = .03). More than 68% (vs 45%) rated their late-life health as excellent or very good, and less than 8% (vs 22%) reported fair or poor health (P < .001 for trend). Regular exercise was associated with significantly better-and smoking and overweight with significantly worse-late-life physical function. Smoking also was associated with a significant decrement in mental function. Modifiable healthy behaviors during early elderly years, including smoking abstinence, weight management, blood pressure control, and regular exercise, are associated not only with enhanced life span in men but also with good health and function during older age.

Duration of Naturally Acquired Antibody Responses to Blood-StagePlasmodium falciparumIs Age Dependent and Antigen Specific

Naturally acquired antibody responses provide partial protection from clinical malaria, and blood-stage parasite vaccines under development aim to prime such responses. To investigate the determinants of antibody response longevity, immunoglobulin G (IgG) antibodies to several blood-stage vaccine candidate antigens in the sera of two cohorts of children of up to 6 years of age during the dry seasons of 2003 and 2004 in The Gambia were examined. The first cohort showed that most antibodies were lost within less than 4 months of the first sampling if a persistent infection was not present, so the study of the second-year cohort involved collecting samples from individuals every 2 weeks over a 3-month period. Antibody responses in the second cohort were also influenced by persistent malaria infection, so analysis focused particularly on children in whom parasites were not detected after the first time point. Antibodies to most antigens declined more slowly in children in the oldest age group (>5 years old) and more rapidly in children in the youngest group (<3 years old). However, antibodies to merozoite surface protein 2 were shorter lived than antibodies to other antigens and were not more persistent in older children. The age-specific and antigen-specific differences were not explained by different IgG subclass response profiles, indicating the probable importance of differential longevities of plasma cell populations rather than antibody molecules. It is likely that young children mostly have short-lived plasma cells and thus experience rapid declines in antibody levels but that older children have longer-lasting antibody responses that depend on long-lived plasma cells.

Mediterranean diet and plasma concentration of inflammatory markers in old and very old subjects in the ZINCAGE population study

Aging is associated with low-grade elevation of circulating inflammatory markers, leading to increased risk of morbidity and mortality. The Mediterranean diet has been suggested as a determinant of longevity. In the current study, we investigated the impact of the Mediterranean diet on inflammatory status in old subjects. Within the ZINCAGE study, 957 healthy old subjects (>or=60 years old) from five European countries were recruited. Plasma interleukin (IL)-6, IL-8, monocyte chemoattractant protein, tumor necrosis factor-alpha, high-density lipoprotein cholesterol (HDL-C) and erythrocyte sedimentation rate (ESR) were measured. Dietary data were collected applying a food frequency questionnaire and were used to estimate adherence to the Mediterranean diet. The Italians presented the greatest adherence to the Mediterranean diet, while the Polish the poorest. In females, higher diet score was significantly associated with lower body mass index and ESR and higher HDL-C levels (beta=-0.127, p=0.003; beta=-0.144, p=0.001; beta=0.144, p=0.029, respectively). In males, diet score was negatively associated with IL-8 levels (beta=-0.101, p=0.044). The Mediterranean diet was associated with reduced IL-8 concentrations in Greeks (beta=-0.213, p=0.007). There were significant effects of the components of the Mediterranean diet on inflammation markers. The Mediterranean diet score is useful in assessing nutritional influence on immune status.

Hormetic Triggers for Intervention in Aging, Disease and Trauma

Hormesis refers to the ability of a chemical or physical agent to condition the physiological state of an organism to tolerate stress with low doses of otherwise harmful agents. Evolutionary evidence shows that the survival and longevity of species hinge on their optimal ability to resist stress challenge. Hormesis is a potent strategy to stimulate latent repair processes to tolerate a specific challenge. Examples of hormetic agent-mimetics, which induce at least partial physiological conditioning, activate known pathways of longevity determinants, i.e., genetic stability, altered metabolism, immunoregulation and stress resistance. Despite the diversity of age-related diseases, glucose and oxidation-mediated protein and DNA damage are common denominators. The associated physiological conditioning-benefits may trigger: 1) activation of latent stress resistance pathways of youthful DNA repair; 2) increased resistance to oxidizing pollutants; 3) improved protein structure and function; 4) improved immunity; 5) damaged tissue remodeling; 6) adjustments in central and peripheral nervous systems; 7) altered metabolism; and 8) delay or breaking of inappropriate protein cross-links. Hormetic mimetics have intervention potential in cancer, diabetes, age-related diseases, infectious diseases, heart and kidney failure, cardiovascular diseases and Alzheimer’s disease. Small nucleotide SOS signals, dipeptides, ethanol, thiols, and metals and conserved peptide sequences found in sharks, frogs, woodchucks, and bears, can regulate cytokines, cellular immunity, and central and peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate, and metabolic pathways. disease sensitivity. Conserved stress mimetics are highlighted here that rejuvenate DNA and proteins repair and thus may intervene in aging, disease, and trauma. Hibernation Induction Trigger mimetics, Deltorphins, emerge as novel hormetic agents, effective both as pre and post exposure to physiological conditioners to tolerate stress, and prevent damage, and delay possibly aging. Hormesis mimetics offer powerful survival strategies, with better control over the beneficial dose response. Combinations of several mimetics may more closely mimic environmental challenges, which stimulate multiple stress responses.

Ammonoid growth rhythms

Determination of ammonite growth rate and longevity is an intriguing but difficult problem. Doguzhaeva (1982) made an exciting contribution through her study of ‘growth rings’ and their distribution on a variety of ammonite shells. She postulated a fortnightly or lunar monthly periodicity for chamber formation and a daily periodicity for growth line secretion on the outer shell. Before these suppositions become doctrine, however, a measure of skepticism seems warranted. Some of the relevant remarks run over familiar ground and were raised in response to Kahn & Pompea (1978), who assumed that growth increments on the outer shell of Nautilus are daily and septal deposition lunar monthly. Criticisms of their work focused on the nature of their data and the lack of a basis for the initial time assumptions (Jones & Thompson 1979; Saunders & Ward 1979). These criticisms apply to Doguzhaeva's study because her approach is similar and because Nautilus is the best living analog for ammonite growth.