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1.  Specificity of cytochemical and fluorescence methods of senescence-associated β-galactosidase detection for ageing driven by replication and time 
Biogerontology  2014;15:407-413.
Senescence-associated β-galactosidase (SA-β-Gal) is a widely used marker of senescent cells in vitro and in vivo. In this report, young and senescent human peritoneal mesothelial cells (HPMCs) and fragments of the omentum, from which these cells were isolated, were subjected to simultaneous examination of SA-β-Gal using two methods, i.e. cytochemical and fluorescent methods. The results obtained were confronted with the cumulative number of population doublings (CPD) and the calendar age of the tissue donor. The study showed that senescence of HPMCs proceeds with either an increased percentage of SA-β-Gal-positive cells or increased enzyme activity. Cytochemical SA-β-Gal staining in early-passage cultures negatively correlated with CPD values but not with donor age in both cell cultures and omentum specimens. Conversely, SA-β-Gal activity measured with the fluorescence method rose in proportion to the calendar age of the donor either in early-passage cultures or in primary cell isolates from omental tissue. At the same time it was not related to the CPD values. These findings may suggest that with respect to at least peritoneal mesothelial cells, the cytochemical and fluorescent methods of SA-β-Gal detection, though complementary, are informative for different levels of aging, i.e. the cytochemical approach for senescence in vitro and the fluorescence-based technique for organismal aging in vivo.
doi:10.1007/s10522-014-9505-4
PMCID: PMC4090812  PMID: 24878779
Aging; Biomarker; Mesothelial cells; Replicative senescence; SA-β-Gal
2.  Links between nucleolar activity, rDNA stability, aneuploidy and chronological aging in the yeast Saccharomyces cerevisiae 
Biogerontology  2014;15:289-316.
The nucleolus is speculated to be a regulator of cellular senescence in numerous biological systems (Guarente, Genes Dev 11(19):2449–2455, 1997; Johnson et al., Curr Opin Cell Biol 10(3):332–338, 1998). In the budding yeast Saccharomyces cerevisiae, alterations in nucleolar architecture, the redistribution of nucleolar protein and the accumulation of extrachromosomal ribosomal DNA circles (ERCs) during replicative aging have been reported. However, little is known regarding rDNA stability and changes in nucleolar activity during chronological aging (CA), which is another yeast aging model used. In the present study, the impact of aberrant cell cycle checkpoint control (knock-out of BUB1, BUB2, MAD1 and TEL1 genes in haploid and diploid hemizygous states) on CA-mediated changes in the nucleolus was studied. Nucleolus fragmentation, changes in the nucleolus size and the nucleolus/nucleus ratio, ERC accumulation, expression pattern changes and the relocation of protein involved in transcriptional silencing during CA were revealed. All strains examined were affected by oxidative stress, aneuploidy (numerical rather than structural aberrations) and DNA damage. However, the bub1 cells were the most prone to aneuploidy events, which may contribute to observed decrease in chronological lifespan. We postulate that chronological aging may be affected by redox imbalance-mediated chromosome XII instability leading to both rDNA instability and whole chromosome aneuploidy. CA-mediated nucleolus fragmentation may be a consequence of nucleolus enlargement and/or Nop2p upregulation. Moreover, the rDNA content of chronologically aging cells may be a factor determining the subsequent replicative lifespan. Taken together, we demonstrated that the nucleolus state is also affected during CA in yeast.
Electronic supplementary material
The online version of this article (doi:10.1007/s10522-014-9499-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s10522-014-9499-y
PMCID: PMC4019837  PMID: 24711086
Yeast; Chronological aging; rDNA stability; Nucleolus; Aneuploidy; Cell cycle checkpoint control
3.  Metabolomic profiling reveals severe skeletal muscle group-specific perturbations of metabolism in aged FBN rats 
Biogerontology  2014;15:217-232.
Mammalian skeletal muscles exhibit age-related adaptive and pathological remodeling. Several muscles in particular undergo progressive atrophy and degeneration beyond median lifespan. To better understand myocellular responses to aging, we used semi-quantitative global metabolomic profiling to characterize trends in metabolic changes between 15-month-old adult and 32-month-old aged Fischer 344 × Brown Norway (FBN) male rats. The FBN rat gastrocnemius muscle exhibits age-dependent atrophy, whereas the soleus muscle, up until 32 months, exhibits markedly fewer signs of atrophy. Both gastrocnemius and soleus muscles were analyzed, as well as plasma and urine. Compared to adult gastrocnemius, aged gastrocnemius showed evidence of reduced glycolytic metabolism, including accumulation of glycolytic, glycogenolytic, and pentose phosphate pathway intermediates. Pyruvate was elevated with age, yet levels of citrate and nicotinamide adenine dinucleotide were reduced, consistent with mitochondrial abnormalities. Indicative of muscle atrophy, 3-methylhistidine and free amino acids were elevated in aged gastrocnemius. The monounsaturated fatty acids oleate, cis-vaccenate, and palmitoleate also increased in aged gastrocnemius, suggesting altered lipid metabolism. Compared to gastrocnemius, aged soleus exhibited far fewer changes in carbohydrate metabolism, but did show reductions in several glycolytic intermediates, fumarate, malate, and flavin adenine dinucleotide. Plasma biochemicals showing the largest age-related increases included glycocholate, heme, 1,5-anhydroglucitol, 1-palmitoleoyl-glycerophosphocholine, palmitoleate, and creatine. These changes suggest reduced insulin sensitivity in aged FBN rats. Altogether, these data highlight skeletal muscle group-specific perturbations of glucose and lipid metabolism consistent with mitochondrial dysfunction in aged FBN rats.
Electronic supplementary material
The online version of this article (doi:10.1007/s10522-014-9492-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10522-014-9492-5
PMCID: PMC4019835  PMID: 24652515
Muscle; Aging; Metabolomics; Sarcopenia; Biomarkers; NAD
4.  A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta 
Biogerontology  2013;15:47-64.
Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are potentially harmful to the organism. Most of the senescence hallmarks were common for both RS and SIPS; however, some differences were observed. 32 % of doxorubicin-treated cells were arrested in the G2/M phase of the cell cycle, while 73 % of replicatively senescing cells were arrested in the G1 phase. Moreover, on the basis of alkaline phosphatase activity measurements, we show that a 7-day treatment with doxorubicin (dox), does not cause precocious cell calcification, which is a characteristic feature of RS. We did not observe calcification even though after 7 days of dox-treatment many other markers characteristic for senescent cells were present. It can suggest that dox-induced SIPS does not accelerate the mineralization of vessels. We consider that detailed characterization of the two types of cellular senescence can be useful in in vitro studies of potential anti-aging factors.
Electronic supplementary material
The online version of this article (doi:10.1007/s10522-013-9477-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10522-013-9477-9
PMCID: PMC3905196  PMID: 24243065
Senescence; VSMCs; Doxorubicin; Aging; Cardiovascular diseases; Calcification
5.  Shared Ageing Research Models (ShARM): a new facility to support ageing research 
Biogerontology  2013;14:789-794.
In order to manage the rise in life expectancy and the concomitant increased occurrence of age-related diseases, research into ageing has become a strategic priority. Mouse models are commonly utilised as they share high homology with humans and show many similar signs and diseases of ageing. However, the time and cost needed to rear aged cohorts can limit research opportunities. Sharing of resources can provide an ethically and economically superior framework to overcome some of these issues but requires dedicated infrastructure. Shared Ageing Research Models (ShARM) (www.ShARMUK.org) is a new, not-for-profit organisation funded by Wellcome Trust, open to all investigators. It collects, stores and distributes flash frozen tissues from aged murine models through its biorepository and provides a database of live ageing mouse colonies available in the UK and abroad. It also has an online environment (MICEspace) for collation and analysis of data from communal models and discussion boards on subjects such as the welfare of ageing animals and common endpoints for intervention studies. Since launching in July 2012, thanks to the generosity of researchers in UK and Europe, ShARM has collected more than 2,500 tissues and has in excess of 2,000 mice registered in live ageing colonies. By providing the appropriate support, ShARM has been able to bring together the knowledge and experience of investigators in the UK and Europe to maximise research outputs with little additional cost and minimising animal use in order to facilitate progress in ageing research.
doi:10.1007/s10522-013-9457-0
PMCID: PMC3847282  PMID: 24085518
Ageing; Murine models; Tissue bank
6.  Tissue resident stem cells: till death do us part 
Biogerontology  2013;14:573-590.
Aging is accompanied by reduced regenerative capacity of all tissues and organs and dysfunction of adult stem cells. Notably, these age-related alterations contribute to distinct pathophysiological characteristics depending on the tissue of origin and function and thus require special attention in a type by type manner. In this paper, we review the current understanding of the mechanisms leading to tissue-specific adult stem cell dysfunction and reduced regenerative capacity with age. A comprehensive investigation of the hematopoietic, the neural, the mesenchymal, and the skeletal stem cells in age-related research highlights that distinct mechanisms are associated with the different types of tissue stem cells. The link between age-related stem cell dysfunction and human pathologies is discussed along with the challenges and the future perspectives in stem cell-based therapies in age-related diseases.
doi:10.1007/s10522-013-9469-9
PMCID: PMC3879821  PMID: 24085521
Adult stem cells; Aging; Regeneration; Age-related diseases; Stem cell therapy
7.  Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD) 
Biogerontology  2013;14:461-482.
Cells in aerobic condition are constantly exposed to reactive oxygen species (ROS), which may induce damage to biomolecules, including proteins, nucleic acids and lipids. In normal circumstances, the amount of ROS is counterbalanced by cellular antioxidant defence, with its main components—antioxidant enzymes, DNA repair and small molecular weight antioxidants. An imbalance between the production and neutralization of ROS by antioxidant defence is associated with oxidative stress, which plays an important role in the pathogenesis of many age-related and degenerative diseases, including age-related macular degeneration (AMD), affecting the macula—the central part of the retina. The retina is especially prone to oxidative stress due to high oxygen pressure and exposure to UV and blue light promoting ROS generation. Because oxidative stress has an established role in AMD pathogenesis, proper functioning of antioxidant defence may be crucial for the occurrence and progression of this disease. Antioxidant enzymes play a major role in ROS scavenging and changes of their expression or/and activity are reported to be associated with AMD. Therefore, the enzymes in the retina along with their genes may constitute a perspective target in AMD prevention and therapy.
doi:10.1007/s10522-013-9463-2
PMCID: PMC3824279  PMID: 24057278
AMD; Oxidative stress; Antioxidant enzymes; Small molecular weight antioxidants; ROS; Retinal pigment epithelium
8.  Antioxidants can extend lifespan of Brachionus manjavacas (Rotifera), but only in a few combinations 
Biogerontology  2012;13(3):261-275.
Animal cells are protected from oxidative damage by an antioxidant network operating as a coordinated system, with strong synergistic interactions. Lifespan studies with whole animals are expensive and laborious, so there has been little investigation of which antioxidant interactions might be useful for life extension. Animals in the phylum Rotifera are particularly promising models for aging studies because they are small (0.1–1 mm), have short, two-week lifespan, display typical patterns of animal aging, and have well characterized, easy to measure phenotypes of aging and senescence. One class of interventions that has consistently produced significant rotifer life extension is antioxidants. Although the mechanism of antioxidant effects on animal aging remains controversial, the ability of some antioxidant supplements to extend rotifer lifespan was unequivocal. We found that exposing rotifers to certain combinations of antioxidant supplements can produce up to about 20% longer lifespan, but that most antioxidants have no effect. We performed life table tests with 20 single antioxidants and none yielded significant rotifer life extension. We tested 60 two-way combinations of selected antioxidants and only seven (12%) produced significant rotifer life extension. None of the 20 three- and four-way antioxidant combinations tested yielded significant rotifer life extension. These observations suggest that dietary exposure of antioxidants can extend rotifer lifespan, but most antioxidants do not. We observed significant rotifer life extension only when antioxidants were paired with trolox, N-acetyl cysteine, l-carnosine, or EUK-8. This illustrates that antioxidant treatments capable of rotifer life extension are patchily distributed in the parameter space, so large regions must be searched to find them. It furthermore underscores the value of the rotifer model to conduct rapid, facile life table experiments with many treatments, which makes such a search feasible. Although some antioxidants extended rotifer lifespan, they likely did so by another mechanism than direct antioxidation.
doi:10.1007/s10522-012-9371-x
PMCID: PMC3760418  PMID: 22270335
Antioxidant; Rotifera; Lifespan; Aging; ROS; l-Carnosine; N-acetyl cysteine; EUK-8; Vitamin E
9.  Assessing biological aging: the origin of deficit accumulation 
Biogerontology  2013;14:709-717.
The health of individuals is highly heterogeneous, as is the rate at which they age. To account for such heterogeneity, we have suggested that an individual’s health status can be represented by the number of health deficits (broadly defined by biological and clinical characteristics) that they accumulate. This allows health to be expressed in a single number: the frailty index (FI) is the ratio of the deficits present in a person to the total number of deficits considered (e.g. in a given database or experimental procedure). Changes in the FI characterize the rate of individual aging. The behavior of the FI is highly characteristic: it shows an age specific, nonlinear increase, (similar to Gompertz law), higher values in females, strong associations with adverse outcomes (e.g., mortality), and a universal limit to its increase (at FI ~0.7). These features have been demonstrated in dozens of studies. Even so, little is known about the origin of deficit accumulation. Here, we apply a stochastic dynamics framework to illustrate that the average number of deficits present in an individual is the product of the average intensity of the environmental stresses and the average recovery time. The age-associated increase in recovery time results in the accumulation of deficits. This not only explains why the number of deficits can be used to estimate individual differences in aging rates, but also suggests that targeting the recovery rate (e.g. by preventive or therapeutic interventions) will decrease the number of deficits that individuals accumulate and thereby benefit life expectancy.
Electronic supplementary material
The online version of this article (doi:10.1007/s10522-013-9446-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s10522-013-9446-3
PMCID: PMC3847281  PMID: 23860844
Health status; Deficit accumulation; Frailty; Fitness-frailty continuum; Mortality; Stochastic process
10.  Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats 
Biogerontology  2013;14:431-442.
It has been suggested that the age-related decrease in the number of neurons in the hippocampus that leads to alterations in brain function, may be associated with an increase in apoptosis due to the reduced secretion of growth hormone (GH) and/or melatonin in old animals. In order to investigate this possibility, male Wistar rats of 22 months of age were divided into three groups. One group remained untreated and acted as the control group. The second was treated with growth hormone (hGH) for 10 weeks (2 mg/kg/d sc) and the third was subjected to melatonin treatment (1 mg/kg/d) in the drinking water for the same time. A group of 2-months-old male rats was used as young controls. All rats were killed by decapitation at more than 24 month of age and dentate gyri of the hippocampi were collected. Aging in the dentate gyrus was associated with an increase in apoptosis promoting markers (Bax, Bad and AIF) and with the reduction of some anti-apoptotic ones (XIAP, NIAP, Mcl-1). Expressions of sirtuin 1 and 2 (SIRT1 and 2) as well as levels of HSP 70 were decreased in the dentate gyrus of old rats. GH treatment was able to reduce the pro/anti-apoptotic ratio to levels observed in young animals and also to increase SIRT2. Melatonin reduced also expression of pro-apoptotic genes and proteins (Bax, Bad and AIF), and increased levels of myeloid cell leukemia-1 proteins and SIRT1. Both treatments were able to reduce apoptosis and to enhance survival markers in this part of the hippocampus.
doi:10.1007/s10522-013-9443-6
PMCID: PMC3739870  PMID: 23852044
Aging; Dentate gyrus; Apoptosis; Sirtuins; Growth hormone; Melatonin
11.  Understanding and combating age-related muscle weakness: MYOAGE challenge 
Biogerontology  2013;14(3):229-230.
doi:10.1007/s10522-013-9438-3
PMCID: PMC3718989  PMID: 23793985
12.  A-to-I RNA editing does not change with age in the healthy male rat brain 
Biogerontology  2013;14:395-400.
RNA editing is a post-transcriptional process, which results in base substitution modifications to RNA. It is an important process in generating protein diversity through amino acid substitution and the modulation of splicing events. Previous studies have suggested a link between gene-specific reductions in adenosine to inosine RNA editing and aging in the human brain. Here we demonstrate that changes in RNA editing observed in humans with age are not observed during aging in healthy rats. Furthermore, we identify a conserved editing site in rats, in Cog3. We propose that either age-related changes in RNA editing are specific to primates or humans, or that they are the manifestation of disease pathology. Since rodents are often used as model organisms for studying aging, these findings demonstrate the importance of understanding species-specific differences in RNA biology during aging.
Electronic supplementary material
The online version of this article (doi:10.1007/s10522-013-9433-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10522-013-9433-8
PMCID: PMC3739863  PMID: 23708854
RNA editing; RNA-seq; Cerebral cortex; Brain aging
13.  Loss of caspase-2 accelerates age-dependent alterations in mitochondrial production of reactive oxygen species 
Biogerontology  2013;14(2):121-130.
Mitochondria are known to be a major source and target of oxidative stress. Oxidative stress increases during aging and is suggested to underlie in part the aging process. We have previously documented an increase in endogenous caspase-2 (casp2) activity in hepatocytes obtained from old (28 months) vs. young mice (5 months). More recently, we have shown that casp2 is activated by oxidative stress and is critical for mitochondrial oxidative stress-induced apoptosis. Since casp2 appears integral to mitochondrial oxidative stress-induced apoptosis, in this study we determined whether loss of casp2 altered the production of mitochondrial reactive oxygen radicals (mROS) as a function of age in intact living hepatocytes. To stimulate mitochondrial metabolic activity, we added a mixture of pyruvate and glutamate to hepatocytes while continuously monitoring endogenous mROS production in the presence or absence of rotenone and/or antimycin A. Our data demonstrate that mROS production and neutralization are compromised in hepatocytes of old mice. Interestingly, casp2 deficient hepatocytes from middle age mice (12 months) had similar mROS neutralization kinetics to those of hepatocytes from old WT mice. Rotenone had no effect on mROS metabolism, whereas antimycin A significantly altered mROS production and metabolism in an age-dependent fashion. Our results indicate that: (1) hepatocytes from young and old mice respond differently to dysfunction of the mitochondrial electron transport chain; (2) age-dependent alterations in mROS metabolism are likely regulated by complex III; and (3) absence of casp2 accelerates age-dependent changes in terms of pyruvate/glutamate-induced mROS metabolism.
doi:10.1007/s10522-013-9415-x
PMCID: PMC3657345  PMID: 23504374
Caspase-2; Mitochondria; Reactive oxygen species; Hepatocytes; Aging
14.  Age-dependent alteration in muscle regeneration: the critical role of tissue niche 
Biogerontology  2013;14(3):273-292.
Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity.
doi:10.1007/s10522-013-9429-4
PMCID: PMC3719007  PMID: 23666344
Sarcopenia; Muscle regeneration; Satellite cells; Tissue niche; Growth factors; Stem cells
15.  Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity 
Biogerontology  2011;13(2):119-131.
Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related decline in telomere length observed in our population to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 3′ flanking region of XRCC6 had significant effects on telomere length. At each bi-allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity (P < 0.003). The frequency of the minor allele was higher in long-lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not affect the association of SIRT1 with exceptional survival. The association of the same variant of SIRT1 with longevity was near significant (P < 0.07) in a second population. These results suggest a potential role of SIRT1 in linking telomere length and longevity. Given the differences between this gene and XRCC6, they point to the distinct impact that alternate pathways of telomere maintenance may have on aging and exceptional survival.
doi:10.1007/s10522-011-9360-5
PMCID: PMC3272146  PMID: 21972126
SIRT1; XRCC6; Ku; Telomeres; Aging; Longevity
16.  Extension of Drosophila lifespan by Rosa damascena associated with an increased sensitivity to heat 
Biogerontology  2011;13(2):105-117.
Rosa damascena, or Damask rose, is a rose hybrid commonly harvested for rose oil used in perfumery and for rose water used to flavor food. The petal extract of R. damascena was recently found to decrease Drosophila melanogaster mortality without impairing reproductive fitness or metabolic rate. Here, we report that R. damascena extended both mean and maximum lifespan of the fly. The extract also protected against oxidative stress in flies, predominantly in females. However, it did not alter mitochondrial respiration or content, superoxide production, or the major antioxidant defenses, superoxide dismutase and catalase. The extract increased survival in both sexes when exposed to reduced iron, though surprisingly, it sensitized both sexes to heat stress (survival at 37° C), and appeared to down-regulate the major heat shock protein HSP70 and the small mitochondrial heat shock protein HSP22, at 25° C and after heat shock (4 hours at 37° C). We hypothesize that R. damascena extends lifespan by protecting against iron, which concomitantly leads to decreased HSP expression and compromising heat tolerance.
doi:10.1007/s10522-011-9357-0
PMCID: PMC3288696  PMID: 21928072
Rosa damascena; botanical extract; heat shock; lifespan; aging
17.  Loss of caspase-2 accelerates age-dependent alterations in mitochondrial production of reactive oxygen species 
Biogerontology  2013;14(2):121-130.
Mitochondria are known to be a major source and target of oxidative stress. Oxidative stress increases during aging and is suggested to underlie in part the aging process. We have previously documented an increase in endogenous caspase-2 (casp2) activity in hepatocytes obtained from old (28 months) vs. young mice (5 months). More recently, we have shown that casp2 is activated by oxidative stress and is critical for mitochondrial oxidative stress-induced apoptosis. Since casp2 appears integral to mitochondrial oxidative stress-induced apoptosis, in this study we determined whether loss of casp2 altered the production of mitochondrial reactive oxygen radicals (mROS) as a function of age in intact living hepatocytes. To stimulate mitochondrial metabolic activity, we added a mixture of pyruvate and glutamate to hepatocytes while continuously monitoring endogenous mROS production in the presence or absence of rotenone and/or antimycin A. Our data demonstrate that mROS production and neutralization are compromised in hepatocytes of old mice. Interestingly, casp2 deficient hepatocytes from middle age mice (12 months) had similar mROS neutralization kinetics to those of hepatocytes from old WT mice. Rotenone had no effect on mROS metabolism, whereas antimycin A significantly altered mROS production and metabolism in an age-dependent fashion. Our results indicate that: (1) hepatocytes from young and old mice respond differently to dysfunction of the mitochondrial electron transport chain; (2) age-dependent alterations in mROS metabolism are likely regulated by complex III; and (3) absence of casp2 accelerates age-dependent changes in terms of pyruvate/glutamate-induced mROS metabolism.
doi:10.1007/s10522-013-9415-x
PMCID: PMC3657345  PMID: 23504374
Caspase-2; Mitochondria; Reactive oxygen species; Hepatocytes; Aging
18.  Glyoxalase I activity and immunoreactivity in the aging human lens 
Biogerontology  2009;10(6):711-720.
Glyoxalase I (GLOI) is the first enzyme of the glyoxalase system that catalyzes the metabolism of reactive dicarbonyls, such as methylglyoxal (MGO). During aging and cataract development, human lens proteins are chemically modified by MGO, which is likely due to inadequate metabolism of MGO by the glyoxalase system. In this study, we have determined the effect of aging on GLOI activity and the immunoreactivity and morphological distribution of GLOI in the human lens. A monoclonal antibody was developed against human GLOI. GLOI immunoreactivity was strongest in the anterior epithelial cells and weaker in rest of the lens. Cultured human lens epithelial cells showed immunostaining throughout the cytoplasm. In the human lens, GLOI activity and immunoreactivity both decreased with age. We believe that this would lead to promotion of MGO-modification in aging lens proteins.
doi:10.1007/s10522-009-9218-2
PMCID: PMC3560407  PMID: 19238574
Glyoxalase I; Monoclonal antibody; Human lens; Aging; Enzyme activity; Enzyme immunoreactivity
19.  Age-specificity and the evolution of senescence: a discussion 
Biogerontology  2012;14(1):99-105.
Senescence evolved because selection pressure declines with age. However, to explain senescence it does not suffice to demonstrate that selection pressure declines. It is also necessary to postulate biological mechanisms that lead to a deteriorated state of the organism at high ages, but not before. This has lead to the invocation of ‘age-specific’ genes or processes, a concept which is prone to be interpreted too freely. Events do not happen after a certain amount of time has passed. They need initiation, which means that senescence is required to be a continuous process. As a result, a change at a particular age cannot arise in isolation from changes at other ages, in particular not in isolation from changes at the ages nearby. These mechanistic constraints are not without consequence for the patterns of mortality and fecundity that can evolve. I conclude that from purely logical considerations, senescence is characterized as continuous rather than age-specific deterioration. These considerations guide (theoretical) research in the direction of investigating how continuous somatic change arises, rather than focusing at age-specific events.
doi:10.1007/s10522-012-9410-7
PMCID: PMC3627019  PMID: 23160710
Disposable soma; Age-specificity; Senescence; Aging; Gene expression
20.  p38 MAPK stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes 
Biogerontology  2012;14(1):47-62.
Werner Syndrome (WS) is a human segmental progeria resulting from mutations in a DNA helicase. WS fibroblasts have a shortened replicative capacity, an aged appearance, and activated p38 MAPK, features that can be modulated by inhibition of the p38 pathway. Loss of the WRNp RecQ helicase has been shown to result in replicative stress, suggesting that a link between faulty DNA repair and stress-induced premature cellular senescence may lead to premature ageing in WS. Other progeroid syndromes that share overlapping pathophysiological features with WS also show defects in DNA processing, raising the possibility that faulty DNA repair, leading to replicative stress and premature cellular senescence, might be a more widespread feature of premature ageing syndromes. We therefore analysed replicative capacity, cellular morphology and p38 activation, and the effects of p38 inhibition, in fibroblasts from a range of progeroid syndromes. In general, populations of young fibroblasts from non-WS progeroid syndromes do not have a high level of cells with an enlarged morphology and F-actin stress fibres, unlike young WS cells, although this varies between strains. p38 activation and phosphorylated HSP27 levels generally correlate well with cellular morphology, and treatment with the p38 inhibitor SB203580 effects cellular morphology only in strains with enlarged cells and phosphorylated HSP27. For some syndromes fibroblast replicative capacity was within the normal range, whereas for others it was significantly shorter (e.g. HGPS and DKC). However, although in most cases SB203580 extended replicative capacity, with the exception of WS and DKC the magnitude of the effect was not significantly different from normal dermal fibroblasts. This suggests that stress-induced premature cellular senescence via p38 activation is restricted to a small subset of progeroid syndromes.
Electronic supplementary material
The online version of this article (doi:10.1007/s10522-012-9407-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s10522-012-9407-2
PMCID: PMC3627027  PMID: 23112078
F-actin stress fibres; SB203580; Human telomerase; Cellular morphology; Human ageing; p38 MAP kinase inhibitors; Werner syndrome
21.  Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data 
Biogerontology  2010;12(2):157-166.
Small sample size of genetic data is often a limiting factor for desirable accuracy of estimated genetic effects on age-specific risks and survival. Longitudinal non-genetic data containing information on survival or disease onsets of study participants for whom the genetic data were not collected may provide an additional “reserve” for increasing the accuracy of respective estimates. We present a novel method for joint analyses of “genetic” (covering individuals for whom both genetic information and mortality/morbidity data are available) and “non-genetic” (covering individuals for whom only mortality/morbidity data were collected) subsamples of longitudinal data. Our simulation studies show substantial increase in the accuracy of estimates in such joint analyses compared to analyses based on genetic subsample alone. Application of this method to analysis of the effect of common apolipoprotein E (APOE) polymorphism on survival using combined genetic and non-genetic subsamples of the Framingham Heart Study original cohort data showed that female, but not male, carriers of the APOE e4 allele have significantly worse survival than non-carriers, whereas empirical analyses did not produce any significant results for either sex.
doi:10.1007/s10522-010-9316-1
PMCID: PMC3352324  PMID: 21193960
model; combining data; Framingham Heart Study; mortality; APOE; sex differences
22.  Exceptional Survivors Have Lower Age Trajectories of Blood Glucose: Lessons from Longitudinal Data 
Biogerontology  2009;11(3):257-265.
Exceptional survival results from complicated interplay between genetic and environmental factors. The effects of these factors on survival are mediated by the biological and physiological variables, which affect mortality risk. In this paper, we evaluated the role of blood glucose (BG) in exceptional survival using the Framingham Heart Study data for the main (FHS) and offspring (FHSO) cohorts. We found that: (i) the average cross-sectional age patterns of BG change over time; (ii) the values of BG level among the longest lived individuals in this study differ for different sub-cohorts; (iii) the longitudinal age patterns of BG differ from those of cross-sectional ones. We investigated mechanisms forming average age trajectories of BG in the FHS cohort. We found that the two curves: one, characterizing the average effects of allostatic adaptation, and another, minimizing mortality risk for any given age, play the central role in this process. We found that the average BG age trajectories for exceptional survivors are closer to the curve minimizing mortality risk than those of individuals having shorter life spans. We concluded that individuals whose age trajectories of BG are located around the curve minimizing chances of premature death at each given age have highest chances of reaching exceptional longevity.
doi:10.1007/s10522-009-9243-1
PMCID: PMC3351103  PMID: 19644762
mortality risk; stochastic process model of aging; allostatic adaptation; age-specific physiological norm; blood glucose; Framingham Heart Study
23.  Senemorphism: a novel perspective on aging patterns and its implication for diet-related biology 
Biogerontology  2012;13(4):457-466.
Aging can be described as the accumulation of changes in organisms over time. Aging in organisms undergoing caloric restriction (CR) is widely considered as a slowed version of aging under ad libitum (AL) conditions. However, here we argue that aging under optimized CR is fundamentally different from aging under AL based on the following facts: (1) Comparing the two dietary groups, several age-related changes run in the opposite direction over time; (2) Switching from an AL to a CR diet clearly reverts (not only delays) several “normal” accumulated changes; (3) major causes of death are as different between both groups as they are between species. These observations support the idea that CR and AL initially modulate different metabolic and physiological programs, which exclusively over time generate two biologically different organisms. Such distinct diet-related senescence is analogous to the divergent aging processes and causes of death observed between castes of social insects, such as queens versus workers (“caste-related-senescence”) and also between breeding versus non-breeding semelparous animals (“reproduction-related-senescence”). All these aging phenotypes are different not because they accumulate changes at a different rate, but because they accumulate different changes over time. Thus, the environment does not simply affect the individual aging rate through stochastic effects (e.g. U.V.) but also modulates the activation of a particular program/strategy that influences lifespan (e.g. caste, calorie intake). We refer to the environment-dependent aging patterns encoded by the genome as “senemorphism”. Based on this idea we propose experimental schemes for aging, evolution and biomedical research.
doi:10.1007/s10522-012-9383-6
PMCID: PMC3407360  PMID: 22555514
Senemorphism; Caloric restriction; Longevity; Biomarkers; Senescence; Evolution
24.  Age-dependent response of murine female bone marrow cells to hyperbaric oxygen 
Biogerontology  2012;13(3):287-297.
Consequences of age on the effects of hyperbaric oxygen (HBO) on bone marrow (BM) derived stem cells and progenitors (SCPs) are largely unknown. We treated 2- and 18-month old C57BL/6 female mice by HBO. Hematopoietic stem cells and progenitors, enumerated as colony-forming units in culture, were doubled only in peripheral leukocytes and BM cells of young mice receiving HBO. In old mice colony-forming unit fibroblast numbers, a measure of mesenchymal stromal cells (MSCs) from BM, were high but unaffected by HBO. To further explore this finding, in BM-MSCs we quantified the transcripts of adipocyte early-differentiation genes peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein-β and fatty-acid binding protein 4; these transcripts were not affected by age or HBO. However, osteoblast gene transcripts runt-related transcription factor 2, osterix (OSX) and alkaline phosphatase (AP) were twofold to 20-fold more abundant in MSCs from old control mice relative to those of young control mice. HBO affected expression of osteoblast markers only in old MSCs (OSX gene expression was reduced by twofold and AP expression was increased threefold). Our data demonstrate the impact of aging on the response of BM SCPs to HBO and indicate the potentially different age-related benefit of HBO in wound healing and tissue remodeling.
doi:10.1007/s10522-012-9373-8
PMCID: PMC3360870  PMID: 22270336
Aging; Hyperbaric oxygen; Hematopoietic progenitor cells; Mesenchymal stromal cells
25.  The maintenance gap: a new theoretical perspective on the evolution of aging 
Biogerontology  2011;13(2):197-201.
One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, ‘maintenance requirement’ has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation. Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms. This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.
doi:10.1007/s10522-011-9362-3
PMCID: PMC3322326  PMID: 22042254
Aging; Natural selection; Maintenance; Disposable soma theory; Evolution; Survival

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