Does anti-aging equal anti-microbial?

Aging is the dominant risk factor for human disease in developed countries. Could it be that a wide variety of disease states all have their origins in a common mechanism? Major signaling pathways that determine the rate of aging, such as the insulin/insulin-like growth factor 1 (IGF-1) pathway, might give clues to the nature of this major disease risk factor. It has now been shown that insulin/IGF-1 signaling influences Caenorhabditis elegans resistance to bacteria in such a way that long-lived worms are stress-resistant and slow to succumb to infection. Perhaps enhanced innate immunity is a feature of genetically determined longevity.     

Ceramide, stress, and a "LAG" in aging

Recent studies have implicated the longevity assurance gene LAG1 in ceramide synthesis. In light of a role for ceramide in yeast and mammalian stress responses and mammalian cellular senescence, important connections are emerging between ceramide and organismal aging. In this Perspective, we examine the evidence for these connections in yeast, Drosophila, and mammals, and speculate on their implications.     

Murine models of life span extension

Mice are excellent experimental models for genetic research and are being used to investigate the genetic component of organismal aging. Several mutant mice are known to possess defects in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) neurohormonal pathway and exhibit dwarfism together with extended life span. Their phenotypes resemble those of mice subjected to caloric restriction. Targeted mutations that affect components of this pathway, including the GH receptor, p66Shc, and the IGF-1 receptor (IGF-1R), also extend life span; mutations that affect IGF-1R or downstream components of the pathway decouple longevity effects from dwarfism. These effects on life span may result from an increased capacity to resist oxidative damage.     

Oxygen? No thanks, I'm on a diet

In yeast and worms, mutations that extend longevity appear to simulate starvation conditions. The daf-2 pathway in worms plays a major role in life-span extension and in entry into the starvation-resistant and low-metabolism dauer phase. In a recent study published in Science Express on 13 June 2002, researchers screened for Caenorhabditis elegans mutants that survive in a low-oxygen environment and identified a number of daf-2 mutants that are resistant to hypoxia. The implications of these results are discussed in this Perspective.     

Of worms, flies, dwarfs, and things that go bump in the night

Studies over the past several years have found that antagonism of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway increases life-span in Caenorhabditis elegans and Drosophila. However, a persistent problem in these studies is the fact that the genetic mutation has effects on the development of the organism as well as on reproductive function. These effects act as potential confounding variables that complicate the interpretation of results. Kenyon and colleagues circumvent these issues by suppressing the insulin/IGF-1-like daf-2 signaling pathway at specific stages in the life-span of C. elegans. The results of their investigation challenge our understanding of the evolution of aging and provide opportunities for future studies in mammalian models.     

Subfield history: use of model organisms in the search for human aging genes

The National Institute on Aging (NIA) started a program in 1993 to identify genes involved in the regulation of longevity in a variety of species, including yeast, nematodes, fruit flies, and mice. The initial success of this program has attracted the interest of many investigators working with these organisms. Of primary interest are single-gene mutants that have identified genes and processes involved in longevity regulation across species. These processes include the insulin-like signaling pathway, stress resistance, and most recently, chromosome and nuclear architecture. Mutations in genes that regulate these processes indirectly are also being identified in this program. The ultimate goal of this program is to extend these results to humans to identify the major biological risk factors for age-related decline of function in human physiological systems.     

Poly(ADP-ribosyl)ation, PARP, and aging

Poly(ADP-ribose) polymerases (PARPs) catalyze the poly(ADP-ribosyl)ation of proteins. This posttranslational modification, as generated by the DNA damage-activated enzymes PARP-1 and -2, has long been known to be involved in DNA repair. Correlative data have suggested an association between DNA damage-induced poly(ADP-ribosyl)ation and mammalian longevity, and this link has recently been strengthened by the discovery of interactions between PARP-1 and the Werner syndrome protein. Emerging additional members of the PARP family display different cellular localizations and are involved in diverse processes such as the regulation of telomere or centrosome function, thereby providing further, independent links between poly(ADP-ribosyl)ation and the aging process.     

Is Akt the mastermind behind age-related heart disease?

Over the past several years, the insulin/insulin-like growth factor (IGF) signaling pathway has become a central figure in the study of organismal aging. Mutations in components of this pathway have led to enhanced longevity in several organisms, but it is still not clear whether and how this pathway contributes to human aging and aging-related diseases. In a new study, Miyauchi and colleagues propose that Akt, a member of the phosphatidylinositol 3-kinase family and a downstream component of the insulin/IGF pathway, plays a central role in the life span of endothelial cells. These findings implicate the insulin/IGF pathway in the development and progression of cardiovascular disease.     

Ticking fast or ticking slow, through Shc must you go?

Circumstantial evidence places the p66 isoform of the adapter protein Shc in a position to mediate the accelerated aging phenotype displayed by mice expressing shortened forms of the tumor suppressor protein p53. We present a model in which p66(shc) may be responsible for integrating signals from the p53 pathway with signals from the insulin-like growth factor-1/Daf pathway in mammals. A full understanding of how interactions between p53 and p66(shc) affect longevity will require the production of animals with mutations in the genes encoding both proteins.     

Insulin-like growth factor 1 receptor polymorphism rs2229765 and circulating interleukin-6 level affect male longevity in a population-based prospective study (Treviso Longeva--TRELONG)

Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based "Treviso Longeva"--TRELONG Study from Italy (n = 668, age range 70-105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose-response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females.     

C. elegans gives the dirt on aging

The worm Caenorhabditis elegans has become a popular model organism for the study of mechanisms involved in aging. The C. elegans life span is controlled by several pathways that have been extensively characterized at the molecular level. These include pathways that regulate metabolism and development (namely, the insulin/IGF-1 pathway), nutrition, mitochondrial activity, and reproduction. Presentations at a recent C. elegans conference add to the growing body of knowledge about the genetic networks that control the complex process of aging and suggest new avenues for further investigations.     

Growth hormone in anti-aging medicine: a critical review

Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based “Treviso Longeva”? TRELONG Study from Italy (n?=?668, age range 70–105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose–response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females.     

On trial

As researchers uncover basic mechanisms that underlie aging, they hope that lessons learned from mice, worms, flies, and other lab denizens will apply to people. Making that leap requires a new set of scientific approaches, from observational studies to the most rigorous of tests, the double-blind, randomized, placebo-controlled clinical trial. Navigating this unique scientific terrain presents new obstacles for basic-science researchers but can provide the ultimate payoff.     

Anti-aging medicine: pitfalls and hopes

Since the beginnings of time humans have searched for a fountain of youth. This has led to many extravagant claims which have been highly profitable for their proponents. This area has become known as anti-aging medicine and has deservedly been frowned upon by the medical establishment. On the other hand, in the last decades dramatic advances in our understanding of the aging process have come from studies in worms, flies and mice. This article reviews some of these advances and places the extravagant claims of anti-aging medicine in perspective. We conclude that a balanced diet of moderate proportions and exercise remain today the only proven fountain of youth.     

Aging in check

The spindle checkpoint monitors the interaction between spindle microtubules and kinetochores to prevent precocious entry into anaphase, delaying this stage of mitosis until all condensed chromosomes have been attached to the mitotic spindle in a bi-oriented manner (so that the two kinetochores associated with a pair of sister chromatids are oriented toward opposite poles of the spindle). In addition to conserved Bub and Mad family members, which are known to function in the spindle checkpoint pathway in organisms ranging from yeast to mammals, two mRNA transport genes, Rae1 and Nup9, are also involved in the spindle checkpoint function in mammals. Biochemically, activated spindle checkpoint components have been shown to suppress the activity of the anaphase promoting complex/cyclosome. It is generally thought that decreased activity of the checkpoint components predisposes cells to chromosomal instability, aneuploidy, and malignant transformation. Interestingly, a recent study has shed light on a new function of the spindle checkpoint components Bub3 and Rae1 in the regulation of aging. Mice with haploinsufficiency of Bub3 and Rae1 have a short life span that is associated with the early onset of aging-related features. The progeroid phenotypes caused by deficiency of Bub3 and Rae1 are tightly linked to precocious activation of cellular senescence, but not apoptotic, programs. Therefore, premature aging, rather than neoplastic transformation, may be the major manifestation of a compromised spindle checkpoint in vivo.     

Is DNA cut out for a long life?

Much attention has been focused on the DNA repair hypothesis of aging. Studies in mammals that seek to test the validity of this model are complicated by both the functional redundancy and the essential nature of genes involved in the repair process. Compared to mammals, the study of DNA repair and aging in yeast has considerably fewer complicating factors. In this Perspective, I discuss results presented in this month's issue of Aging Cell that address whether the types of DNA damage repaired by the base excision repair pathway cause aging in yeast.     

Breaking in a new function for casein kinase 2

DNA damage response mechanisms help ensure the fidelity of chromosomal transmission, and the failure of such mechanisms might lead to premature aging and cancer. A new report has established that casein kinase 2 (CK2), a protein that functions in diverse cellular processes, controls the activity of the DNA repair protein XRCC1. These results indicate that CK2 is a key participant in the cellular response to DNA damage.     

Epigenetic regulation of aging in honeybee workers

Aging and longevity are complex life history traits that are influenced by both genes and environment and exhibit significant phenotypic plasticity in a broad range of organisms. A striking example of this plasticity is seen in social insects, such as ants and bees, where different castes can have very different life spans. In particular, the honeybee worker offers an intriguing example of environmental control on aging rate, because workers are conditionally sterile and display very different aging patterns depending on which temporal caste they belong to (hive bee, forager, or a long-lived caste capable of surviving for several months on honey alone). The ubiquitous yolk protein vitellogenin appears to play a key role in the regulatory circuitry that controls this variation. Here we outline the current understanding of the relation between vitellogenin and somatic maintenance in honeybee workers, and how this relation can be understood in a life history context.     

Vitamin B1 blocks damage caused by hyperglycemia

Diabetes accelerates the aging process and leads to complications that include blindness, renal failure, nerve damage, stroke, and cardiovascular disease. It has been hypothesized that high plasma glucose concentrations are responsible for increased mitochondrial free radical production and subsequent inactivation of glyceraldehyde phosphate dehydrogenase (GAPDH) in vascular endothelial cells and other cells implicated in these complications. As a result of the decreased ability of GAPDH to process upstream metabolites, three pathways of metabolic damage are activated, which include the advanced glycation end-product formation pathway, the protein kinase C pathway, and the hexosamine pathway. All three pathways have been implicated in abnormal cell signaling in diabetes. A group of German and U.S. scientists has now found that treating diabetic rats with high doses of benfotiamine, a lipid-soluble form of vitamin B1, can prevent diabetic retinopathy and all three forms of metabolic damage by stimulating transketolase activity and thus diverting excess metabolites toward the pentose pathway. Although vitamin B1 is available over the counter, the researchers at this time do not advocate self-treatment without further clinical data.