Palaeobiology of an extinct Ice Age mammal: Stable isotope and cementum analysis of giant deer teeth

The extinct giant deer, Megaloceros giganteus, is among the largest and most famous of the cervids. Megaloceros remains have been uncovered across Europe and western Asia. but the highest concentrations come from Irish bogs and caves Although Megaloceros has enjoyed a great deal of attention over the centuries, paleobiological study has focused oil morphometric and distributional work until now. This paper presents quantitative data that have implications for understanding its sudden extirpation in western Europe during a period of global climate change approximately 10.600 C-14 years ago (ca 12,500 calendar years BP). We report here the first stable isotope analysis of giant deer teeth. which we combine with dental cementum accretion in order to document age, diet and life-history seasonality from birth until death Enamel delta C-13 and delta O-18 measured in the second and third molars from seven individual giant deer Suggest a grass and forbbased diet supplemented with browse in a deteriorating. possibly water-stressed, environment, and a season of birth around spring/early summer Cementurm data indicate that the ages of the specimens ranged from 6.5 to 14 years and that they possessed mature antlers by autumn, similar to extant cervids. In addition. the possibility for combining these two techniques in future mammalian paleoccological studies is considered. The data presented in this study imply that Megoloceros would have indeed been vulnerable to extirpation during the terminal Pleistocene in Ireland. and this information is relevant to understanding the broader pattern of its extinction.

Body Mass Index Is More Predictive of Progenitor Number in Bone Marrow Stromal Cell Population Than Age in Men: Expanding the Predictors of the Progenitor Compartment

Research has focused on in vitro expansion of bone marrow stromal cells with the aim of developing cell-based therapies or tissue-engineered constructs. There is debate over whether there is a reduction in stem cells/osteoprogenitors in the bone marrow compartment with increasing age. The aim of this study was to investigate patient factors that affect the progenitor pool in bone marrow samples. Six milliliters of marrow aspirate was obtained from the femoral canal of 38 primary hip replacement patients (aged 28-91). Outcome measures were total nucleated cell count, colony-forming efficiency, alkaline phosphatase expression, and expression of stem cell markers. There was a nonsignificant negative correlation between age and both colony-forming efficiency and stem cell marker expression. However, body mass index showed a positive, significant correlation with colony area and number in men-accounting for up to 75% of the variation. In conclusion, body mass index, not age, was highly predictive of the number of progenitors found in bone marrow, and this relationship was sex specific. These results may inform the clinician's treatment choice when considering bone marrow-based therapies. Further, it highlights the need to widen research into patient factors that affect the adult stem cell population beyond age and reinforces the need to consider sexes separately.

Age-specific reproductive investment in female burying beetles: independent effects of state and risk of death

1.How much should an individual invest in reproduction as it grows older? Answering this question involves determining whether individuals measure their age as the time left for future reproduction or as the rate of deterioration in their state. Theory suggests that in the former case individuals should increase their allocation of resources to reproduction as opportunities for future breeding dwindle, and terminally invest when they breed for the last time. In the latter case they should reduce their investment in reproduction with age, either through adaptive reproductive restraint or as a passive by-product of senescence.
2.Here we present the results of experiments on female burying beetles, Nicrophorus vespilloides, in which we independently manipulated the perceived risk of death (by activating the immune system) and the extent of deterioration in state (by changing age of first reproduction and/or prior investment in reproduction).
3.We found that the risk of death and state each independently influenced the extent of reproductive investment. Specifically, we found a state-dependent decline in reproductive investment as females grew older that could be attributed to both adaptive reproductive restraint and senescence. A perceived increase in the risk of death, induced by activation of the immune system, caused females to switch from a strategy of reproductive restraint to terminal investment. Nevertheless, absolute reproductive investment was lower in older females, indicating constraints of senescence.
4.Our results show that a decline in reproductive investment with age does not necessarily constitute evidence of reproductive senescence but can also result from adaptive reproductive restraint.
5.Our results further suggest that the extent of reproductive investment is dependent on several different intrinsic cues and that the particular blend of cues available at any given age can yield very different patterns of investment. Perhaps this explains why age-related reproductive investment patterns seen in nature are so diverse.

Multiplex analysis of age-related protein and lipid modifications in human Bruch's membrane

Aging of the human retina is characterized by progressive pathology, which can lead to vision loss. This progression is believed to involve reactive metabolic intermediates reacting with constituents of Bruch's membrane, significantly altering its physiochemical nature and function. We aimed to replace a myriad of techniques following these changes with one, Raman spectroscopy. We used multiplexed Raman spectroscopy to analyze the age-related changes in 7 proteins, 3 lipids, and 8 advanced glycation/lipoxidation endproducts (AGEs/ALEs) in 63 postmortem human donors. We provided an important database for Raman spectra from a broad range of AGEs and ALEs, each with a characteristic fingerprint. Many of these adducts were shown for the first time in human Bruch's membrane and are significantly associated with aging. The study also introduced the previously unreported up-regulation of heme during aging of Bruch's membrane, which is associated with AGE/ALE formation. Selection of donors ranged from ages 32 to 92 yr. We demonstrated that Raman spectroscopy can identify and quantify age-related changes in a single nondestructive measurement, with potential to measure age-related changes in vivo. We present the first directly recorded evidence of the key role of heme in AGE/ALE formation.

The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes

We examined the ability of pyridoxamine (PM), an inhibitor of formation of advanced glycation end products (AGEs) and lipoxidation end products (ALEs), to protect against diabetes-induced retinal vascular lesions. The effects of PM were compared with the antioxidants vitamin E (VE) and R-alpha-lipoic acid (LA) in streptozotocin-induced diabetic rats. Animals were given either PM (1 g/l drinking water), VE (2,000 IU/kg diet), or LA (0.05%/kg diet). After 29 weeks of diabetes, retinas were examined for pathogenic changes, alterations in extracellular matrix (ECM) gene expression, and accumulation of the immunoreactive AGE/ALE N-epsilon-(carboxymethyl)lysine (CML). Acellular capillaries were increased more than threefold, accompanied by significant upregulation of laminin immunoreactivity in the retinal microvasculature. Diabetes also increased mRNA expression for fibronectin (2-fold), collagen IV (1.6-fold), and laminin beta chain (2.6-fold) in untreated diabetic rats compared with nondiabetic rats. PM treatment protected against capillary drop-out and limited laminin protein upregulation and ECM mRNA expression and the increase in CML in the retinal vasculature. VE and LA failed to protect against retinal capillary closure and had inconsistent effects on diabetes-related upregulation of ECM mRNAs. These results indicate that the AGE/ALE inhibitor PM protected against a range of pathological changes in the diabetic retina and may be useful for treating diabetic retinopathy.

Advanced glycation: an important pathological event in diabetic and age related ocular disease

The formation of advanced glycation end products (AGEs) is a key pathophysiological event with links to a range of important human diseases. It is now clear that AGEs may act as mediators, not only of diabetic complications(1 2) but also of widespread age related pathology such as Alzheimer's disease,(3) decreased skin elasticity,(4) (5) male erectile dysfunction,(6) (7) pulmonary fibrosis,(8) and atherosclerosis.(9 10) Since many cells and tissues of the eye are profoundly influenced by both diabetes and ageing, it is fitting that advanced glycation is now receiving considerable attention as a possible modulator in important visual disorders. An increasing number of reports confirm widespread AGE accumulation at sites of known ocular pathology and demonstrate how these products mediate crosslinking of long lived molecules in the eye. Such studies also underscore the putative pathophysiological role of advanced glycation in ocular cell dysfunction in vitro and in vivo.

Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats

Advanced glycation end products (AGEs), formed from the nonenzymatic glycation of proteins and lipids with reducing sugars, have been implicated in many diabetic complications; however, their role in diabetic retinopathy remains largely unknown. Recent studies suggest that the cellular actions of AGEs may be mediated by AGE-specific receptors (AGE-R). We have examined the immunolocalization of AGEs and AGE-R components R1 and R2 in the retinal vasculature at 2, 4, and 8 months after STZ-induced diabetes as well as in nondiabetic rats infused with AGE bovine serum albumin for 2 weeks. Using polyclonal or monoclonal anti-AGE antibodies and polyclonal antibodies to recombinant AGE-R1 and AGE-R2, immunoreactivity (IR) was examined in the complete retinal vascular tree after isolation by trypsin digestion. After 2, 4, and 8 months of diabetes, there was a gradual increase in AGE IR in basement membrane. At 8 months, pericytes, smooth muscle cells, and endothelial cells of the retinal vessels showed dense intracellular AGE IR. AGE epitopes stained most intensely within pericytes and smooth muscle cells but less in basement membrane of AGE-infused rats compared with the diabetic group. Retinas from normal or bovine-serum-albumin-infused rats were largely negative for AGE IR. AGE-R1 and -R2 co-localized strongly with AGEs of vascular endothelial cells, pericytes, and smooth muscle cells of either normal, diabetic, or AGE-infused rat retinas, and this distribution did not vary with each condition. The data indicate that AGEs accumulate as a function of diabetes duration first within the basement membrane and then intracellularly, co-localizing with cellular AGE-Rs. Significant AGE deposits appear within the pericytes after long-term diabetes or acute challenge with AGE infusion conditions associated with pericyte damage. Co-localization of AGEs and AGE-Rs in retinal cells points to possible interactions of pathogenic significance.

Elevated AGE-modified ApoB in sera of euglycemic, normolipidemic patients with atherosclerosis: relationship to tissue AGEs.:relationship to tissue AGEs

BACKGROUND: Advanced glycation endproducts (AGEs) are implicated in the pathogenesis of atherosclerotic vascular disease of diabetic and nondiabetic etiology. Recent research suggests that advanced glycation of ApoB contributes to the development of hyperlipidemia. AGE-specific receptors, expressed on vascular endothelium and mononuclear cells, may be involved in both the clearance of, and the inflammatory responses to AGEs. The aim of this study was to examine whether there is a relationship between serum AGE-ApoB and AGEs in arterial tissue of older normolipidemic nondiabetic patients with occlusive atherosclerotic disease, compared with age-matched and younger asymptomatic persons.

MATERIALS AND METHODS: Serum AGE-ApoB was measured by ELISA in 21 cardiac bypass patients. Furthermore, an AGE-specific monoclonal antibody, and polyclonal antibodies against anti-AGE-receptor (anti-AGE-R) 1 and 2 were used to explore the localization and distribution of AGEs and AGE-R immunoreactivity (IR) in arterial segments excised from these patients.

RESULTS: Serum AGE-ApoB levels were significantly elevated in the asymptomatic, older population, compared with those in young healthy persons (259 +/- 24 versus 180 +/- 21 AGE U/mg of ApoB, p < 0.01). Higher AGE-ApoB levels were observed in those patients with atherosclerosis (329 +/- 23 versus 259 +/- 24 AGE U/mg ApoB, p < 0.05). Comparisons of tissue AGE-collagen with serum AGE-ApoB levels showed a significant correlation (r = 0.707, p < 0.01). In early lesions, AGE-IR occurred mostly extracellularly. In fatty streaks and dense, cellular atheromatous lesions, AGE-IR was visible within lipid-containing smooth muscle cells and macrophages, while in late-stage, acellular plaques, AGE-IR occurred mostly extracellularly. AGE-R1 and -R2 were observed on vascular endothelial and smooth-muscle cells and on infiltrating mononuclear cells in the early-stage lesions, whereas in dense, late-stage plaques, they colocalized mostly with lipid-laden macrophages. On tissue sections, scoring of AGE-immunofluorescence correlated with tissue AGE and plasma AGE-ApoB.

CONCLUSIONS: (1) The correlation between arterial tissue AGEs and circulating AGE-ApoB suggests a causal link between AGE modification of lipoproteins and atherosclerosis. AGE-specific receptors may contribute to this process. (2) Serum AGE-ApoB may serve to predict atherosclerosis in asymptomatic patients.