Determines Life Span Research Articles

CD47 as a promising therapeutic target in oncology.

CD47 is ubiquitously expressed on the surface of cells and plays a critical role in self-recognition. By interacting with SIRPα, TSP-1 and integrins, CD47 modulates cellular phagocytosis by macrophages, determines life span of individual erythrocytes, regulates activation of immune cells, and manipulates synaptic pruning during neuronal development. As such, CD47 has recently be regarded as one of novel innate checkpoint receptor targets for cancer immunotherapy. In this review, we will discuss increasing awareness about the diverse functions of CD47 and its role in immune system homeostasis. Then, we will discuss its potential therapeutic roles against cancer and outlines, the possible future research directions of CD47- based therapeutics against cancer.

An overview of recent advancements in anti-aging medicines

The phenomenon of aging is most common to all living organisms and its definition is the loss or reduction of the ability to reproduce offspring and the slowly decrease in physical fitness. The current aging population is considered to be a major burden of the 21st century. Therefore, in order to slow the process of aging and maintain the health of the elderly, the discovery of new antiaging medicine remains a top priority. Several well-known researchers are working on this issue which is considered to be a multi-billions of dollars industry in future. Institutes like CRG with scientists like Nicholas Stroustrup and David Sinclair and many others have discovered some advancement in this regard, and looking forward for many more to come, some of these advancements are being described below. The aging process makes death increasingly possible, but it has a stochastic aspect that produces a wide distribution of life span even in homogeneous populations. Studying this stochastic behavior could link molecular mechanisms to the aging process that determines life span. Therefore, C. elegans appears to be involved in physiological aspects that consistently respond to multiple interventions. The existence of invariant dynamics of organism aging in genetic and environmental contexts provides the basis for new quantitative frameworks to assess how and to what extent specific molecular processes contribute to the aspects of aging that determine lifespan. Others are Nutraceuticals, Telomerase, Calorie restriction, Thymus rejuvenating, and effects of some drugs as anti-aging.

Aging, arterial stiffness, and hypertension.

Although the etiology of essential hypertension remains unknown, it is clear that multiple factors may contribute to the pathogenesis of hypertension. Hypertension is an outcome of the interaction of multiple genetic and environmental factors. Several epidemiological studies indicated that the incidence of arterial stiffness and hypertension and related cardiovascular disease (stroke, myocardial infarction) is higher in the aged than in the young population.1–4 The prevalence of arterial stiffening and hypertension increases with age.1,5 Based on an epidemiological study,6 the prevalence of hypertension is more than doubled in the elderly than in the young population. More than two-thirds of individuals after 65 years of age experience hypertension according to the Seventh Report of the Joint National Committee (JNC-7).7 Therefore, it is generally thought that hypertension is an aging disorder. In recent years, metabolic syndrome and hypertension are increasingly seen in the middle-aged and young populations. In these subpopulations, insulin resistance and overproduction of adipokines impair endothelial and heart function leading to early and accelerated cardiovascular aging. It was reported that premature aging (progeria) is associated with accelerated vascular stiffening or vascular aging.8 Aging is defined as the age-related decline in physiological function essential for survival and fertility. Cardiovascular aging is an important factor that determines life span. The wall of large conduit arteries, especially aorta, thicken and lose elasticity over time, and this process results in an increase in pulse wave velocity, an important and reliable measure of arterial stiffness. The increased arterial stiffness, whatever its underlying causes, would reduce the reservoir/buffering function of the conduit arteries near the heart and increase pulse wave velocity, both of which increase systolic and pulse pressure. Therefore, aging-related hypertension is characterized by a significant increase in systolic blood pressure with no change or even a …

Explaining International Fertility Differences*

Why do fertility rates vary so much across countries? Why are European fertility rates so much lower than American fertility rates? To answer these questions we extend the Barro—Becker framework to incorporate the decision to accumulate human capital (which determines earnings) and health capital (which determines life span). We find that cross-country differences in productivity and taxes go a long way toward explaining the observed differences in fertility and mortality.

Age-related transcriptional changes in gene expression in different organs of mice support the metabolic stability theory of aging

Individual differences in the rate of aging are determined by the efficiency with which an organism transforms resources into metabolic energy thus maintaining the homeostatic condition of its cells and tissues. This observation has been integrated with analytical studies of the metabolic process to derive the following principle: The metabolic stability of regulatory networks, that is the ability of cells to maintain stable concentrations of reactive oxygen species (ROS) and other critical metabolites is the prime determinant of life span. The metabolic stability of a regulatory network is determined by the diversity of the metabolic pathways or the degree of connectivity of genes in the network. These properties can be empirically evaluated in terms of transcriptional changes in gene expression. We use microarrays to investigate the age-dependence of transcriptional changes of genes in the insulin signaling, oxidative phosphorylation and glutathione metabolism pathways in mice. Our studies delineate age and tissue specific patterns of transcriptional changes which are consistent with the metabolic stability–longevity principle. This study, in addition, rejects the free radical hypothesis which postulates that the production rate of ROS, and not its stability, determines life span.Electronic supplementary materialThe online version of this article (doi:10.1007/s10522-008-9197-8) contains supplementary material, which is available to authorized users.

The Mitochondrial Free Radical Theory of Aging: A Critical View

The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA. At its most orthodox MFRTA proposes that these free radicals damage mitochondrial DNA (mtDNA) and in turn provoke mutations that alter mitochondrial function (e.g. ATP production). According to this, oxidative damage to mtDNA negatively correlates with maximum life span in mammals. However, in contrast to MFRTA predictions, high levels of oxidative damage in mtDNA do not decrease longevity in mice. Moreover, mice with alterations in polymerase gamma (the mitochondrial DNA polymerase) accumulate 500 times higher levels of point mutations in mtDNA without suffering from accelerated aging. Dietary restriction (DR) is the only non-genetic treatment that clearly increases mean and maximum life span. According to MFRTA caloric restricted animals produce fewer mitochondrial reactive oxygen species (mtROS). However, DR alters more than free radical production (e.g. it decreases insulin signalling) and therefore the increase in longevity cannot be exclusively attributed to a decrease in mtROS generation. Thus, moderate exercise produces similar changes in free radical production and oxidative damage without increasing maximum life span. In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.

The Stress of Aging

Laurent et al . present new evidence for a role of the transcription factor JunD in protection of cells against oxidative stress, which may in turn have effects on organismal aging. JunD, which functions as a subunit of the AP1 transcription factor, is thought to protect cells from oxidative damage by regulating transcription of genes whose products function in antioxidant defense or production of H 2 O 2 . The ability of cells to tolerate oxidative stress is thought to be an important factor that determines life span, and the insulin and insulin-like growth factor signaling pathways (inhibition of which can lead to enhanced life span) regulate Foxo transcription factors, which are linked to resistance to oxidative stress. With these connections in mind, Laurent et al . monitored life span of JunD –/– mice. The mice showed about a 15% decrease in mean or maximal life spans compared with those of wild-type littermates. Analysis of metabolic parameters showed that the mutant animals had enhanced insulin secretion and consequent hypoglycemia along with inactivation of FoxO1. Some of the authors had earlier shown that depletion of JunD could influence angiogenesis by altering expression of vascular endothelial growth factor A (VEGF-A), so they tested whether alterations in angiogenesis at the pancreas might contribute to the hyperinsulinemia of the mutant animals. Indeed, in JunD –/– pancreatic β cells, expression of hypoxia-inducible factor 1α was increased and led to increased production of VEGF-A, and the pancreatic islets of the mutant animals showed increased vascularization. The authors propose that increased oxidative stress in the JunD –/– animals may lead to these effects in the pancreas, an idea supported by an experiment in which long-term treatment of animals with the antioxidant N -acetylcysteine reduced pancreatic angiogenesis and restored normal blood concentrations of glucose and insulin in the mutant animals. The authors thus propose to have outlined a pathway by which the JunD protein may have a role in promoting longevity through protection from oxidative stress. G. Laurent, F. Solari, B. Mateescu, M. Karaca, J. Castel, B. Bourachot, C. Magnan, M. Billaud, F. Mechta-Grigoriou, Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling. Cell Metab. 7 , 113-124 (2008). [PubMed]

C. elegansortholog of mammalian Ku70 interacts with insulin‐like signaling to modulate stress resistance and life span

The mammalian Ku heterodimer has important roles in DNA double strand break repair, telomere maintenance, cell cycle checkpoint-arrest, tumor suppression, and cellular stress resistance. To investigate the evolutionarily conserved functions of Ku, we knocked down expression by RNA interference (RNAi) of Ku genes in C. elegans. We found that C. elegans Ku70 (CKU-70) is required for resistance to genotoxic stress, regulates cytotoxic stress responses, and influences aging. The latter effects are dependent on an IGF-1/insulin-like signaling pathway previously shown to affect life span. Reduction of CKU-70 activity amplifies the aging phenotype of long-lived insulin receptor daf-2 mutations in a daf-16-dependent manner. These observations support the view that organismal stress resistance determines life span and Ku70 modulates these effects.

Retinoic acid determines life span of leukemic cells by inducing antagonistic apoptosis-regulatory programs

As a single signal, retinoids induce terminal differentiation. This implies that they activate differentiation and apoptosis in a temporally defined order to allow expression of the differentiated phenotype well before death. We report that two apparently contradictory retinoid-induced programs have the capacity to define cellular life span. Anti-apoptotic factors are activated concomitantly with differentiation, while retinoids induce at the same time also pro-apoptotic signaling. We have assessed the roles of two key factors, Bcl2A1 and TRAIL, in the temporal programming of cell death and differentiation. We demonstrate that PLB985 are type II cells in which TRAIL induces apoptosis through the extrinsic and – via Bid activation – also the intrinsic death pathways. Bcl2A1, ectopically over-expressed, or endogenously induced by retinoic acid receptor agonists, protected cells from apoptosis triggered by TRAIL, whose induction required the activation of both the retinoic acid and retinoid X receptors. Bcl2A1 prevented loss of mitochondrial membrane potential and caspase-9, but not caspase-8, activation. The expression of anti-sense Bcl2A1 sensitized PLB985 cells to TRAIL. Co-culture experiments revealed protection from fraternicide if sister cells were pre-exposed to retinoic acid. Collectively, our data support a model in which retinoids orchestrate a life span-regulatory program comprising Bcl2A1 induction to temporally protect against concomitantly induced TRAIL death signaling. Termination of this life span in presence of Bcl2A1 is most likely a consequence of the Bid-independent TRAIL action. Thus, depending on the retinoic acid and retinoid X receptor activation potential of a ligand and the relative efficacies of the intrinsic and extrinsic death pathways in a given cell, a single retinoid triggers the life span of a differentiated phenotype.

Becoming Oldest-Old: Evidence from Historical U.S. Data

We argue that the environment determines life span, using historical data to show that such indicators of environmental insults in early childhood and young adulthood as quarter of birth, residence, occupation, wealth, and the incidence of specific infectious diseases affected older age mortality. Consistent with improvements in early life factors, we find that the effect of quarter of birth on older age mortality has diminished over the twentieth century and that the declining impact of quarter of birth explains 16 to 17 percent of the difference in ten year mortality rates of Americans age 60-79 in 1900 and in 1960-1980. We estimate that at least one-fifth of the increase between 1900 and 1999 in the probability of a 65 year old surviving to age 85 may be attributable to early life conditions. We also present suggestive evidence on the mortality trajectory of the oldest old in the first half of the twentieth century that implies that the shape of the mortality trajectory, though not its level, has remained constant.

Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans.

In the nematode Caenorhabditis elegans, dauer formation, stress resistance, and longevity are determined in part by DAF-2 (insulin receptor-like protein), AGE-1 (phosphatidylinositol-3-OH kinase catalytic subunit), and DAF-16 (forkhead transcription factor). Mutations in daf-2 and age-1 result in increased resistance to heat, oxidants, and UV. We have discovered that daf-2 and age-1 mutations result in increased Cd and Cu ion resistance in a 24 h toxicity assay. Lethal concentration (LC50) values for Cd and Cu ions in daf-2 and age-1 mutants were significantly (P<0.001) higher than in wild-type nematodes. However, LC50 values in daf-16;age-1 mutants were not significantly different, implying that metal resistance is influenced by a DAF-16-related function. As metallothionein (MT) proteins play a major role in metal detoxification, we examined the expression of MT genes both under noninducing conditions and after exposure to sublethal and acute heavy metal stress. MT1 mRNA levels were significantly (P<0.05) higher in daf-2 mutants compared to age-1 mutants and wild-type C. elegans under basal conditions. After 10 mM Cd treatment, induction of MT1 and MT2 mRNA was three- and twofold higher, respectively, in daf-2 mutant worms than in wild-type. However, a sublethal concentration of Cd (0.1 mM) resulted in even higher (three- to sevenfold) levels of both MT mRNAs in all strains. Cu did not induce MT1 or MT2 mRNAs. These results are consistent with a model in which the insulin-signaling pathway determines life span through regulation of stress protein genes

Extending life – a lifestyle choice

Conventional wisdom teaches that calorie restriction acts to increase longevity by reducing the metabolic rate and lowering the levels of reactive oxygen species that cause macromolecular damage. In a novel twist Lin et al. 1. Lin S-J. et al. Requirement of NAD and Sir2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000; 289: 2126-2128 Crossref PubMed Scopus (1477) Google Scholar link calorie restriction to the SIR locus in yeast, which mediates genomic silencing at telomeres, and propose a molecular mechanism by which this regimen causes increased longevity. Silencing at telomeres by Sir2p determines life span by triggering the deacetylation of specific lysines at the N terminus of histones, resulting in silenced chromatin. Sir2p has been shown to display NAD+-dependent histone deacetylase activity, thus creating a potential link between metabolism and ageing.

The RAS genes: a homeostatic device in Saccharomyces cerevisiae longevity☆

The genetic analysis of the yeast replicative life span has revealed the importance of metabolic control and resistance to stress. It has also illuminated the pivotal role in determining longevity that the RAS genes play by the maintenance of homeostasis. This role appears to be performed by the coordination of a variety of cellular processes. Metabolic control seems to occupy a central position among these cellular processes that include stress resistance. Some of the features of metabolic control in yeast resemble the effects of the daf pathway for adult longevity in Caenorhabditis elegans and the metabolic consequences of selection for extended longevity in Drosophila melanogaster, as well as some of the features of caloric restriction in mammals. The distinction between dividing and nondividing cells is proposed to be less important for the aging process than generally believed because these cell types are part of a metabolic continuum in which the total metabolic capacity determines life span. As a consequence, the study of yeast aging may be helpful in understanding processes occurring in the aging brain.

Calendar life span versus budding lifespan of Saccharomyces cerevisiae

This investigation is concerned with the internal factors governing the life span of individual yeast cells. The life span may be limited either by the number of buds a cell can produce or by internal measurement of metabolic time. The natural relationship between the number of cells a single cell can produce and the passage of time was modified by three different kinds of treatment: (1) by cooling the cells for several hours each day; (2) by preculturing the cells in media which inhibit cell division before allowing logarithmic growth; and (3) by culturing the cells in a medium which reduces the rate of budding. All these methods led to a prolongation of chronological life span, but the life span measured by the number of buddings remained remarkably constant. We therefore conclude that there is some kind of factor involved in the budding process which determines life span.