Aging

Age-related resistance of skeletal muscle-derived progenitor cells to SPARC may explain a shift from myogenesis to adipogenesis Abstract Aging causes phenotypic changes in skeletal muscle progenitor cells (SMPCs) that lead to the loss of myogenicity and adipogenesis. Secreted protein acidic and rich in cysteine (SPARC), which is secreted from SMPCs, stimulates myogenesis and inhibits adipogenesis. The present study aimed to examine whether changes in SPARC expression, its signaling pathway, or both are involved in age-related phenotypic changes in SMPCs. SPARC expression levels were comparable in SMPCs derived from young and old rats. However, when SPARC expression was reduced by a SPARC-specific siRNA, SMPCs from young rats showed reduced myogenesis and increased adipogenesis. In striking contrast, old rats showed little changes in these functions. Recombinant SPARC was effective in inhibiting adipogenesis and promoting myogenesis of SMPCs from young rats but had no effect on SMPCs fr

Accelerated aging syndromes, are they relevant to normal human aging Abstract Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely af

Indy knockdown in mice mimics elements of dietary restriction. A new mouse knock-out of the Indy gene sheds light on the mechanisms by which a reduction in Indy may lead to a healthier life. Mutations in the Indy gene (for I’m not dead yet) were first described in flies where they dramatically extend life span without a loss in fertility, physical activity, flight velocity or metabolic rate [1, 2]. The Indy gene codes for a high-affinity dicarboxylate/citrate plasma membrane transporter found most abundantly at the plasma membrane of adult fat body, oenocytes and midgut cells, the primary sites of intermediary metabolism in the fly [3]. In support of the hypothesis that the Indy mutation might be altering metabolism in a manner similar to dietary restriction (DR), it has been shown that DR downregulates Indy in normal flies and that Indy long-lived flies share several phenotypes with long-lived DR flies, including decreased insulin-like signaling, lipid storage, weight gain, and resist

Progeria, rapamycin and normal aging: recent breakthrough Abstract A recent discovery that rapamycin suppresses a pro-senescent phenotype in progeric cells not only suggests a non-toxic therapy for progeria but also implies its similarity with normal aging. For one, rapamycin is also known to suppress aging of regular human cells. Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria. In the last week paper in  Science Transl Med , Francis Collins, Dimitri Krainc, Kan Cao and co-workers described that rapamycin reverses cellular phenotypes in Hutchinson-Gilford progeria syndrome (HGPS) cells [ 1 ]. Is it a co-incidence that rapamycin also suppresses senescence in regular (non-HGPS) mammalian cells [ 2 ]? Clearance of progerin by rapamycin Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by some features remi

New comparative genomics approach reveals a conserved health span signature across species Abstract Environmental and genetic interventions extend health span in a range of organisms by triggering changes in different specific but complementary pathways. We investigated the gene expression changes that occur across species when health span is extended via different interventions. To perform this comparison using heterogeneous datasets from different measurement platforms and organisms, we developed a novel non-parametric methodology that can detect statistical significance of overlaps in ranked lists of genes, and estimate the number of genes with a common expression profile. By comparing genetic and environmental interventions that consistently lead to increased health span in invertebrates and vertebrates we built a conserved health span signature and described how such a signature depends on tissue type. Furthermore, we examined the relationship between calorie restriction and resve

Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes Abstract The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al.,  Aging  2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer. Introduction In a recent issue of Aging, Dubrovsky et al. [ 1 ] describe the effects of disruption of the Clock gene on lifespan and health in mice. They report that CLOCK-deficient mice have reduced average and maximum lifespan, and have increased incidence of dermatitis and cat

Put on your thinking cap:  G‐quadruplexes, helicases, and telomeres Understanding how G-quadruplex (G4) DNA structures that form in G-rich tracts of the genome affect chromosomal stability and processes such as copying the genetic information (DNA replication) or decoding the information (RNA transcription) has posed a significant challenge to researchers in the field. Although historically there has been some controversy over the existence of G4 DNA structures in vivo, emerging evidence suggests that they are indeed likely to form and have cellular consequences. In a recent study, Smith et al. investigated a role of G4 DNA in telomere capping [1], i.e., the adaptation of a nucleoprotein structure that prevents the chromosomal DNA ends from being recognized as DNA breaks and protects them from becoming degraded or fused. Telomere capping is a fairly complex process since a number of proteins have been shown to bind telomeric single-stranded or double-stranded DNA at the chromosome end.