Dietary methylmercury and fatty acids affect the lipid metabolism of adipose tissue and liver in rainbow trout.

Methylmercury (MeHg) is a pervasive environmental contaminant in aquatic ecosystems that can reach elevated concentrations in fish of high trophic levels, such as salmonids. The present study aims at investigating the individual and combined impacts of dietary MeHg and fatty acids on lipid metabolism in juvenile rainbow trout (Oncorhynchus mykiss) with a focus on two key organs, adipose tissue and liver. MeHg and fatty acids are both known to act on energy homeostasis although little is known about their interplay on lipid metabolism in fish. Fish were fed diets enriched in linoleic acid (LA, 18:2 n-6), α-linolenic acid (ALA, 18:3 n-3), eicosapentaenoic acid (EPA, 20:5 n-3) or docosahexaenoic acid (DHA, 22:6 n-3) for ten weeks, with the addition of MeHg to the diets during the last six weeks (0, 2.4 or 5.5 mg MeHg/kg dry matter). LA and ALA are polyunsaturated fatty acids (PUFA) typical of plant-derived oils whereas EPA and DHA are n-3 long chain PUFA largely found in fish oil, all used in feed formulation in aquaculture. The results showed that the LA-enriched diet induced a higher whole-body lipid content compared to the three other diets. On the contrary, the addition of MeHg led to a significant reduction of the whole-body lipid content, regardless of the diet. Interestingly, the adipocytes were larger both in presence of LA, compared to EPA and DHA, or MeHg, indicating a lipogenic effect of these two compounds. No effect was, however, observed on lipid accumulation per gram of adipose tissue. The fatty acid composition of adipose tissue and liver was significantly modified by the dietary lipids, reflecting both the fatty acid composition of the diets and the high bioconversion capacity of the rainbow trout. Exposure to MeHg selectively led to a release of n-6 PUFA from the hepatic membranes of fish fed the LA-enriched diet, showing a disruption of the pathways using n-6 PUFA. This study highlights the significant impact of MeHg exposure and dietary fatty acids on lipid metabolism in fish. Further investigation is needed to elucidate the underlying mechanisms and to explore the potential involvement of other organs.

Filtration performance, fit test and side effects of respiratory personal protective equipment following decontamination: Observations for user safety and comfort.

OBJECTIVE: While facing personal protective equipment (PPE) shortages during the COVID-19 pandemic, several institutions looked to PPE decontamination and reuse options. This study documents the effect of two hydrogen peroxide treatments on filtration efficiency and fit tests as well as the side effects for volunteers after the decontamination of N95 filtering facepiece respirators (FFRs). We also propose an efficient and large-scale treatment protocol that allows for the traceability of this protective equipment in hospitals during PPE shortages. METHODS: The effects of low-temperature hydrogen peroxide sterilization and hydrogen peroxide vapor (HPV) on two FFR models (filtration, decontamination level, residual emanation) were evaluated. Ten volunteers reported comfort issues and side effects after wearing 1h FFRs worn and decontaminated up to five times. RESULTS: The decontamination process does not negatively affect FFR efficiency, but repeated use and handling tend to lead to damage, limiting the number of times FFRs can be reused. Moreover, the recommended 24-h post-treatment aeration does not sufficiently eliminate residual hydrogen peroxide. Prolonged aeration time increased user comfort when using decontaminated FFRs. CONCLUSIONS: HPV and low-temperature hydrogen peroxide sterilization seem to be appropriate treatments for FFR decontamination when the PPE is reused by the same user. PPE decontamination and reuse methods should be carefully considered as they are critical for the comfort and safety of healthcare workers.

Beyond the Lab: What We Can Learn about Cancer from Wild and Domestic Animals.

Cancer research has benefited immensely from the use of animal models. Several genetic tools accessible in rodent models have provided valuable insight into cellular and molecular mechanisms linked to cancer development or metastasis and various lines are available. However, at the same time, it is important to accompany these findings with those from alternative or non-model animals to offer new perspectives into the understanding of tumor development, prevention, and treatment. In this review, we first discuss animals characterized by little or no tumor development. Cancer incidence in small animals, such as the naked mole rat, blind mole rat and bats have been reported as almost negligible and tumor development may be inhibited by increased defense and repair mechanisms, altered cell cycle signaling and reduced rates of cell migration to avoid tumor microenvironments. On the other end of the size spectrum, large animals such as elephants and whales also appear to have low overall cancer rates, possibly due to gene replicates that are involved in apoptosis and therefore can inhibit uncontrolled cell cycle progression. While it is important to determine the mechanisms that lead to cancer protection in these animals, we can also take advantage of other animals that are highly susceptible to cancer, especially those which develop tumors similar to humans, such as carnivores or poultry. The use of such animals does not require the transplantation of malignant cancer cells or use of oncogenic substances as they spontaneously develop tumors of similar presentation and pathophysiology to those found in humans. For example, some tumor suppressor genes are highly conserved between humans and domestic species, and various tumors develop in similar ways or because of a common environment. These animals are therefore of great interest for broadening perspectives and techniques and for gathering information on the tumor mechanisms of certain types of cancer. Here we present a detailed review of alternative and/or non-model vertebrates, that can be used at different levels of cancer research to open new perspectives and fields of action.

The Catechins Profile of Green Tea Extracts Affects the Antioxidant Activity and Degradation of Catechins in DHA-Rich Oil.

This study investigated the effect of the catechins profile on the antioxidant activity of green tea extracts (GTEs) by comparing the antioxidant activity of an EGC-rich GTE (GTE1, catechin content: 58% EGC, 30.1% EGCG, 7.9% EC, and 3.9% ECG) and an EGCG-rich GTE (GTE2, catechin content: 60.6% EGCG, 17.7% EGC, 11.8% ECG, and 9.8% EC) in a DHA-rich oil. The effects of the individual catechins (EGC, EC, EGCG, and ECG) and reconstituted catechins mixtures (CatMix), prepared to contain the same amount of major catechins as in the GTEs, were also measured. All treatments (GTE1, CatMix1, GTE2, CatMix2, EGC250, EC250, EGCG250, and ECG250), each containing epistructured catechins at a concentration of 250 ppm, as well as the control (oil with no added antioxidant), were stored at 30 °C for 21 days with sampling intervals of 7 days. The antioxidant activity was assessed by measuring the peroxide value (PV) and p-anisidine value (p-AV) of oils. Changes in fatty acid content and catechins content were also monitored. Both GTEs enhanced the oxidative stability of the DHA-rich oil, but GTE1 demonstrated a stronger antioxidant activity than GTE2. No significant difference was observed between the PV of treatments with GTE1 and CatMix1 during storage, whereas the PV of oil with GTE2 was significantly higher than that with CatMix2 after 21 days. Among the individual catechins, EGC was the strongest antioxidant. Overall, the antioxidant activities of the extracts and catechins were observed in the decreasing order GTE1 ≈ EGC250 ≈ CatMix1 > GTE2 > EGCG250 ≈ CatMix2 > ECG250 > EC250. A significant change in fatty acid content was observed for the control and EC250 samples, and the catechins were most stable in GTE1-supplemented oil. Our results indicate that the EGC-rich GTE is a more potent antioxidant in DHA-rich oil than the EGCG-rich GTE.

Comparative evaluation of Panther Fusion and real-time PCR for detection of Burkholderia pseudomallei in spiked human blood.

Introduction. Melioidosis is an infection that most commonly presents with bacteraemia. Culture-based laboratory methods can result in a significant delay to organism identification. Molecular diagnostic techniques have a high sensitivity and rapid time to diagnosis. A decreased time to diagnosis is likely to improve patient outcomes. Aim. To compare the Panther Fusion automated molecular instrument to an in-house method for the detection of Burkholderia pseudomallei directly from spiked human whole-blood samples. Results. The in-house method detected 11/12 (92 %) samples with a B. pseudomallei concentration of 2.5-4.5×102 c.f.u. ml-1. The Panther was less reliable, detecting only 8/14 (75 %) samples with a similar bacterial concentration. The Panther was able to detect 12/12 (100 %) spiked blood culture-positive samples. Conclusion. The direct detection of B. pseudomallei from patient blood on presentation to a healthcare facility will significantly decrease time to diagnosis. We describe an in-house real-time PCR method with the lowest reported limit of detection to date. Due to lower sensitivity, the Panther Fusion would be best used as a diagnostic method directly from a positive blood culture.

Punicic Acid Triggers Ferroptotic Cell Death in Carcinoma Cells.

Plant-derived conjugated linolenic acids (CLnA) have been widely studied for their preventive and therapeutic properties against diverse diseases such as cancer. In particular, punicic acid (PunA), a conjugated linolenic acid isomer (C18:3 c9t11c13) present at up to 83% in pomegranate seed oil, has been shown to exert anti-cancer effects, although the mechanism behind its cytotoxicity remains unclear. Ferroptosis, a cell death triggered by an overwhelming accumulation of lipid peroxides, has recently arisen as a potential mechanism underlying CLnA cytotoxicity. In the present study, we show that PunA is highly cytotoxic to HCT-116 colorectal and FaDu hypopharyngeal carcinoma cells grown either in monolayers or as three-dimensional spheroids. Moreover, our data indicate that PunA triggers ferroptosis in carcinoma cells. It induces significant lipid peroxidation and its effects are prevented by the addition of ferroptosis inhibitors. A combination with docosahexaenoic acid (DHA), a known polyunsaturated fatty acid with anticancer properties, synergistically increases PunA cytotoxicity. Our findings highlight the potential of using PunA as a ferroptosis-sensitizing phytochemical for the prevention and treatment of cancer.

Green Tea Extract Enhances the Oxidative Stability of DHA-Rich Oil.

Docosahexaenoic acid (DHA) is one of the most important omega-3 polyunsaturated fatty acids, with proven health-promoting properties. However, oils with a very high content in DHA (DHAO) are extremely susceptible to oxidation, which affects shelf stability and limits incorporation in food products. Green tea extracts (GTE) are potential candidates for the protection of these oils, but their use in such oils has not been previously reported. This study investigated the effect of GTE (160 ppm, 400 ppm, 1000 ppm) and α-tocopherol (80 ppm, 200 ppm, 500 ppm) on the oxidative stability of a DHAO over a 9-week storage at 30 °C. The oxidative status was monitored during storage by the measurement of peroxide value (PV) and p-anisidine value (p-AV). Changes in eicosapentaenoic acid (EPA) and DHA content, as well as in catechins and tocopherol contents, were also evaluated. The addition of GTE enhanced the oxidative stability of DHAO by reducing the formation of peroxides and secondary oxidation products, whereas α-tocopherol had no significant effect on the PV of oil during storage but led to a significantly higher p-AV. The EPA and DHA content of DHAO was stable in GTE-supplemented samples whereas a decrease was observed in the control and α-tocopherol-supplemented samples. GTE also delayed the degradation of tocopherols initially present in the oil, while catechins resulting from the addition of GTE decreased progressively during the storage period.

Lack of Differences in Inflammation and T Cell-Mediated Function between Young and Older Women with Obesity.

Both obesity and aging are associated with dysregulated immune and inflammatory responses. There is limited knowledge, however, on differences in the immune system between young and older adults with obesity. The goal of this study was to compare circulating inflammatory cytokines and T cell-mediated immune response between young and older women with obesity. Twenty-three young (23-43 years) and 21 older (60-83 years) women with obesity were recruited at the Weight and Wellness Center at Tufts Medical Center. Circulating inflammatory cytokines (CRP, IL-6, and IL-1ß) and ex vivo indicators of T cell-mediated immune function were compared between the groups. Older women with obesity had significantly fewer circulating CD3+, CD8+, CD19+, and natural killer T (NKT) cells compared to young women with obesity (p = 0.016, p < 0.0001, p = 0.0003, and p < 0.0001, respectively). However, with few exceptions, there was no significant difference in inflammation markers or stimulated lymphocyte proliferation and cytokine production by peripheral blood mononuclear cells between young and older participants. These findings are in contrast to those previously reported in young and old subjects with healthy weight and call for further investigation into the impact of obesity on premature aging of the immune system.

CD34 regulates the skeletal muscle response to hypoxia.

Chronic obstructive pulmonary disease (COPD) can sometimes be associated with skeletal muscle atrophy. Hypoxemic episodes, which occur during disease exacerbation and daily physical activity, are frequent in COPD patients. However, the link between hypoxemia and muscle atrophy remains unclear, along with mechanisms of muscle hypoxic stress response. Myogenic progenitors (MPs) and fibro/adipogenic progenitors (FAPs) express CD34 and participate to muscle mass maintenance. Although there is evidence linking CD34 expression and muscle repair, the link between CD34 expression, muscle wasting and the hypoxic stress observed in COPD has never been studied. Using a 2-day model of exposure to hypoxic conditions, we investigated the impact of hypoxia on skeletal muscle wasting and function, and elucidated the importance of CD34 expression in that response. A 2-day exposure to hypoxic conditions induces muscle atrophy, which was significantly worse in Cd34-/- mice compared to wild type (WT). Moreover, the lack of CD34 expression negatively impacts the maximal strength of the extensor digitorum longus muscle in response to hypoxia. Following exposure to hypoxic conditions, FAPs (which support MPs differentiation and myogenesis) are significantly lower in Cd34-/- mice compared to WT animals while the expression of myogenic regulatory factors and degradation factors (Atrogin) are similar. CD34 expression is important in the maintenance of muscle mass and function in response to hypoxic stress. These results highlight a new potential role for CD34 in muscle mass maintenance in hypoxic stress such as observed in COPD.

Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice.

Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.

Mild Suppression of Hyperinsulinemia to Treat Obesity and Insulin Resistance.

Insulin plays roles in lipid uptake, lipolysis, and lipogenesis, in addition to controlling blood glucose levels. Excessive circulating insulin is associated with adipose tissue expansion and obesity, yet a causal role for hyperinsulinemia in the development of mammalian obesity has proven controversial, with many researchers suggesting it as a consequence of insulin resistance. Recently, evidence that specifically reducing hyperinsulinemia can prevent and reverse obesity in animal models has been presented. Our experiments, and others in this field, question the current dogma that hyperinsulinemia is a response to obesity and/or insulin resistance. In this review, we discuss preclinical evidence in the context of the broader literature and speculate on the possibility of clinical translation of alternative approaches for treating obesity.

Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

Excess circulating insulin is associated with obesity in humans and in animal models. However, the physiologic causality of hyperinsulinemia in adult obesity has rightfully been questioned because of the absence of clear evidence that weight loss can be induced by acutely reversing diet-induced hyperinsulinemia. Herein, we describe the consequences of inducible, partial insulin gene deletion in a mouse model in which animals have already been made obese by consuming a high-fat diet. A modest reduction in insulin production/secretion was sufficient to cause significant weight loss within 5 wk, with a specific effect on visceral adipose tissue. This result was associated with a reduction in the protein abundance of the lipodystrophy gene polymerase I and transcript release factor ( Ptrf; Cavin) in gonadal adipose tissue. RNAseq analysis showed that reduced insulin and weight loss also associated with a signature of reduced innate immunity. This study demonstrates that changes in circulating insulin that are too fine to adversely affect glucose homeostasis nonetheless exert control over adiposity.-Page, M. M., Skovsø, S., Cen, H., Chiu, A. P., Dionne, D. A., Hutchinson, D. F., Lim, G. E., Szabat, M., Flibotte, S., Sinha, S., Nislow, C., Rodrigues, B., Johnson, J. D. Reducing insulin via conditional partial gene ablation in adults reverses diet-induced weight gain.

Proteostasis and ageing: insights from long-lived mutant mice.

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis - where proteostasis is defined here as the maintenance of the proteome - appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants.

A causal role for hyperinsulinemia in obesity.

Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces ß Cell Proliferation.

Pancreatic ß cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive ß cells into more pliable states with reduced cellular insulin levels, increased ß cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, ß cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses ß cell proliferation in a cell-autonomous manner.

Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress.

Reduced signalling through the insulin/insulin-like growth factor-1 signalling (IIS) pathway is a highly conserved lifespan determinant in model organisms. The precise mechanism underlying the effects of the IIS on lifespan and health is currently unclear, although cellular stress resistance may be important. We have previously demonstrated that mice globally lacking insulin receptor substrate 1 (Irs1(-/-) ) are long-lived and enjoy a greater period of their life free from age-related pathology compared with wild-type (WT) controls. In this study, we show that primary dermal fibroblasts and primary myoblasts derived from Irs1(-/-) mice are no more resistant to a range of oxidant and nonoxidant chemical stressors than cells derived from WT mice.

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage.

Insulin receptor substrate-1 null (Irs1 (-/-)) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 (-/-) and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 (-/-) mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 (-/-) mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 (-/-) mice, although the hepatic GSH/GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 (-/-) mice. Overall, our results do not support the premise that lifespan extension in Irs1 (-/-) mice is associated with greater tissue antioxidant protection or reduced oxidative damage.

A comparative cellular and molecular biology of longevity database.

Discovering key cellular and molecular traits that promote longevity is a major goal of aging and longevity research. One experimental strategy is to determine which traits have been selected during the evolution of longevity in naturally long-lived animal species. This comparative approach has been applied to lifespan research for nearly four decades, yielding hundreds of datasets describing aspects of cell and molecular biology hypothesized to relate to animal longevity. Here, we introduce a Comparative Cellular and Molecular Biology of Longevity Database, available at ( http://genomics.brocku.ca/ccmbl/ ), as a compendium of comparative cell and molecular data presented in the context of longevity. This open access database will facilitate the meta-analysis of amalgamated datasets using standardized maximum lifespan (MLSP) data (from AnAge). The first edition contains over 800 data records describing experimental measurements of cellular stress resistance, reactive oxygen species metabolism, membrane composition, protein homeostasis, and genome homeostasis as they relate to vertebrate species MLSP. The purpose of this review is to introduce the database and briefly demonstrate its use in the meta-analysis of combined datasets.

Dietary restriction increases skeletal muscle mitochondrial respiration but not mitochondrial content in C57BL/6 mice.

Dietary restriction (DR) is suggested to induce mitochondrial biogenesis, although recently this has been challenged. Here we determined the impact of 1, 9 and 18 months of 30% DR in male C57BL/6 mice on key mitochondrial factors and on mitochondrial function in skeletal muscle, relative to age-matched ad libitum (AL) controls. We examined proteins and mRNAs associated with mitochondrial biogenesis and measured mitochondrial respiration in permeabilised myofibres using high resolution respirometry. 30% DR, irrespective of duration, had no effect on citrate synthase activity. In contrast, total and nuclear protein levels of PGC-1α, mRNA levels of several mitochondrial associated proteins (Pgc-1α, Nrf1, Core 1, Cox IV, Atps) and cytochrome c oxidase content were increased in skeletal muscle of DR mice. Furthermore, a range of mitochondrial respiration rates were increased significantly by DR, with DR partially attenuating the age-related decline in respiration observed in AL controls. Therefore, DR did not increase mitochondrial content, as determined by citrate synthase, in mouse skeletal muscle. However, it did induce a PGC-1α adaptive response and increased mitochondrial respiration. Thus, we suggest that a functionally 'efficient' mitochondrial electron transport chain may be a critical mechanism underlying DR, rather than any net increase in mitochondrial content per se.

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan.

Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities. Although UV damage repair has been shown to correlate positively with mammalian species lifespan, we lack similar insight into many other DNA repair pathways, including base excision repair (BER). DNA is continuously exposed to reactive oxygen species produced during aerobic metabolism, resulting in the occurrence of oxidative damage within DNA. Short-patch BER plays an important role in repairing the resultant oxidative lesions. We therefore tested whether an enhancement of BER enzyme activities has occurred concomitantly with the evolution of increased maximum lifespan (MLSP). We collected brain and liver tissue from 15 vertebrate endotherm species ranging in MLSP over an order of magnitude. We measured apurinic/apyrimidinic (AP) endonuclease activity, as well as the rates of nucleotide incorporation into an oligonucleotide containing a single nucleotide gap (catalyzed by BER polymerase ß) and subsequent ligation of the oligonucleotide. None of these activities correlated positively with species MLSP. Rather, nucleotide incorporation and oligonucleotide ligation activities appeared to be primarily (and negatively) correlated with species body mass.