The scientific debate on longevity and its determinants is lively and involves researchers from different disciplines. Finding a clear cut explanation for why some people live longer than others is not an easy task as longevity proves to be connected to more than one factor. Moreover, variables that are shown to be significant for longer survival in certain populations are not always relevant to individuals of other populations. Recently, researchers have identified in Sardinia the Blue Zone (BZ), thus denominated due to the significant number of cases of centenarians recorded as well as a low sex ratio value. This points to an exceptional favourable longevity of males when compared with the expected values in developed countries. A village located in this area was selected for the carrying out of a more detailed analysis at individual level and socio-demographic determinants of longevity were examined. A family reconstructed database was created using a multi-source approach, as this data collection strategy allowed for careful cross-checking of the data, thus guaranteeing data of high quality as well as an exceptionally high level of coverage of known survival. Historical data was therefore used to study today’s population, establishing a unique bridge between historical demography and the current level of longevity. The study focused on survival of newborns in the selected village during a period of 50 years – from 1866 to 1915 – and also took into consideration information on related family members. Each individual included in the database was followed from birth to death, as he/she went through marriage and family formation. Complete survival of all newborns was observed until the present. Based on careful review of the existing literature, the empirical model considered factors such as sex differential, the contribution of familial transmission both in terms of genes, biological, and shared environment, and the role played by environment operationalised considering early-life conditions. Concepts were organized into a life-course approach for survival analysis. The analysis of the data enabled to the estimation of mortality trajectories, which in turn confirmed the exceptional longevity of the population understudy and in particular of males. The investigation of differential survival among members of the same community brought to light the relevance of certain familial variables on survival, which are not exclusively genetic. The results achieved open the way to further studies.

Birth (BW) (n = 1,107) and weaning weight (WW) (n = 1,024), pregnancy rate (PR) (n = 1,255), calf crop born (CCB) (n = 1,232), calf crop weaned (CCW) (n = 1,225), and cow??s weight at palpation (CW) (n = 1,403) were evaluated from 1994 to 2004 in 143 F1 females who were sired by Brahman (B), Boran (Bo), and Tuli (T) bulls and who were out of Angus and Hereford cows. In 2004, mouth scores (MS) (n = 71) were assigned to the remaining females. PR, CCB, CCW, CW, and BCS were evaluated using a model that consisted of sire of dam breed, dam of dam breed, and calf??s birth year/age of dam as fixed effects. Sire of dam within sire breed of dam and dam within sire of dam within sire breed of dam were used as random effects. BW and WW were analyzed using the same model including calf??s gender. Two-way interactions were tested for significance. Year/age was significant for all traits (P < 0.05). Adjusted means for BW for calves out of cows by B, Bo, and T sires were 35.66, 35.38, and 35.59 kg respectively, and were not different (P > 0.05). Adjusted means for WW for calves out of cows by B, Bo, and T sires were 233.4, 220.1, and 208.2 kg respectively, and were significantly different. For both BW and WW, male calves were heavier (P < 0.05) than females. Adjusted means for PR for females sired by B, Bo, and T bulls were 0.914, 0.945, and 0.920, and were not different (P > 0.05). Adjusted means for CCB for females sired by B, Bo, and T bulls were 0.890, 0.943, and 0.910 respectfully, and Bo was higher (P < 0.05) than B. CCW showed the same ranking as CCB with adjusted means of 0.834, 0.887, and 0.857 for cows by B, Bo, and T bulls, with Bo being higher (P < 0.05) than B. CW adjusted means, in the fall of 2002, were 594.29, 519.38, and 517.3 kg. B-sired females were heavier (P < 0.05) than Bo- or T- sired cows. More Bo- (P = 0.013) and B-sired (P = 0.003) cows had solid mouths in 2004 than T-sired cows.

As life expectancy in the United States increases each year, the percentage of the population that is comprised of aged individuals rises also. Researchers expect the largest increase in population to occur in the segment consisting of individuals 85 and older. Thus, investigations of the aging process, with the goals of further extending average life expectancy and improving the quality of life for aged individuals, have become increasingly important to our society. To better understand the genetics of aging, we elected to utilize another model organism, the domestic dog. The benefit to this work is that breeds exhibit extreme, natural variation in life expectancies. Here I report my contributions towards establishing the dog as another model organism for investigations of the aging process. Multiple linear regression analysis was carried out to determine the association between life spans and breed size in the dog, based upon data derived from the American pet population. A negative correlation was observed between both height and longevity and between weight and longevity with weight being the significant predictor of life span. Fifty-four genes implicated in the aging process were mapped to the canine genome. These genes were selected because of their demonstrated contribution to longevity in other organisms or based upon their proximity to a marker, D4S1564, on human chromosome 4. Four genes that are associated with dwarf mice and extended life span were analyzed in nine dog breeds of varying sizes and life expectancies. Fifty-three polymorphisms were discovered in Ghr, Ghrhr, Pit1, and Prop1. Thirteen ancestral SNPs were discovered in which both alleles were found in every breed. In Ghrhr, a transition mutation was found that changes the amino acid sequence as well as the function of the protein and is statistically significant (p=4.8 x 10-6) when large dogs are compared to medium-sized breeds, but not when they are compared to small breeds (p=0.001). This SNP warrants further investigation in additional dogs and breeds.

Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2003. / Includes bibliographical references (leaves 258-273). Also available in electronic version. Access restricted to campus users.

Data from the Quebec swine breeding program (1980 to 2001) were used to estimate genetic parameters for longevity and to evaluate the contribution of non-genetic factors. After data verifications, there were 28,377 Yorkshire, 30,123 Landrace and 7,830 Duroc sows with records of herd life. The program 'The Survival Kit V3.12' (Ducrocq and Solkner, 2001) was used to estimate heritability separately within each breed, using a Cox proportional hazard model. The time-independent fixed effects of age at first service and of the combinations of herd with year of birth, estimated breeding value (EBV) backfat, EBV age to 100 kilograms and EBV litter size were included. The effects of number of piglets born, number of piglets weaned, crossbreeding at insemination, stage of sow (farrowing, weaning or heat) and their combination with parity were treated as fixed time-dependent variables whereas herd by year was treated as random time-dependent variable. The random effect of sire using sire relationships back two generations was considered as the source of genetic variation. Length of productive life (longevity) was defined as the number of days from first service until culling.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Biology. Title from thesis description page. Advisor: Tarynn Witten. Includes bibliographical references.

Lungs donated after cardiac death (DCD) are an underutilized resource for a dwindling donor lung transplant pool. Our study investigates the potential of a novel preservation solution, Somah, to better preserve statically stored DCD lungs, for an extended time period, when compared to low-potassium dextran solution (LPD). We hypothesize that Somah is a metabolically superior organ preservation solution for hypothermic statically stored porcine DCD lungs, possibly improving lung transplant outcomes. Porcine DCD lungs (n = 3 per group) were flushed with and submerged in cold preservation solution. The lungs were stored up to 12 h, and samples were taken from lung tissue and the preservation medium throughout. Metabolomic and redox potential were analyzed using high performance liquid chromatography, mass spectrometry, and RedoxSYS (R), comparing substrate and pathway utilization in both preservation solutions. Glutathione reduction was seen in Somah but not in LPD during preservation. Carnitine, carnosine, and n-acetylcarnosine levels were elevated in the Somah medium compared with LPD throughout. Biopsies of Somah exposed lungs demonstrated similar trends after 2 h, up to 12 h. Adenosine gradually decreased in Somah medium over 12 h, but not in LPD. An inversely proportional increase in inosine was found in Somah. Higher oxidative stress levels were measured in LPD. Our study suggests suboptimal metabolic preservation in lungs stored in LPD. LPD had poor antioxidant potential, cytoprotection, and an insufficient redox potential. These findings may have immediate clinical implications for human organs; however, further investigation is needed to evaluate DCD lung preservation in Somah as a viable option for transplant.

Aging is a major risk factor for many chronic diseases and a complex biological phenomenon. The most well studied and characterized pathways involved in metabolism and known to regulate longevity include sirtuins, AMP-activated protein kinase, insulin-like growth factor (IGF) and the mechanistic target of rapamycin (mTOR).1 These signaling pathways and related transcriptional factors are evolutionarily conserved from yeast to primates. Evidence suggests adipose tissue plays an important role in the regulation of lifespan particularly through energy homeostasis during times of scarcity and excess. Our laboratory has shown adipose triglyceride lipase (ATGL), the rate-limiting enzyme within the lipolytic pathway, is the target of dietary restriction and insulin/IGF-1 signaling pathways, both of which regulate lifespan.22 Given the convergence and necessity of ATGL-1 in the longevity response of dietary restriction and reduced insulin/IGF1 signaling pathways and the uncertainty of the downstream effects TOR has on longevity, we hypothesize that ATGL-1 plays an important role in CeTOR regulated longevity in C. elegans. This investigation was carried out by (a) determining whether levels of ATGL-1 are influenced by TOR inhibition via rapamycin and TOR specific RNA interference (RNAi) and (b) examining the role of ATGL-1 in CeTOR regulated longevity in C. elegans. We have found that rapamycin treatment does not increase expression of ATGL-1::GFP in C. elegans, however, continued research with CeTOR inhibition using rapamycin and RNAi treatment is necessary. The RNAi and longevity experiments need to be conducted. Tissue specific regulation of ATGL expression has been shown to be implicated in chronic disease and in longevity. However, there are still many insights to be discovered and understood about its role in longevity pathways, including feedback mechanisms and second messengers lipolytic products play. Elucidating the downstream effects of ATGL within model organisms will impact future chronic disease research and longevity studies. Given that these pathways are widely evolutionarily conserved, future findings will aid in understanding longevity regulatory mechanisms in humans.

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