-
[
International Worm Meeting,
2019]
Senescence (i.e. aging) is the greatest cause of disease worldwide, yet its underlying causes are still not well understood. The discovery in the 1980s of C. elegans mutants with greatly extended lifespan was very exciting. Not only did it imply the existence of core mechanisms of aging as a whole, but also their presence in a highly tractable model organism suggested that the study of C. elegans could quickly reveal the secret of ageing. When I entered the field in 1993, I imagined that this would take 5-10 years at most. It was soon discovered by the Ruvkun and Kenyon labs that the largest effects on lifespan are exerted by the insulin/IGF-1 signaling (IIS) pathway, acting through a potent inhibitor of aging: the FoxO transcription factor DAF-16. But identifying the aging process that DAF-16 controls has proven to be surprisingly difficult. My talk will present the results of recent attempts by my group to understand the DAF-16 roadblock, and get beyond it to discover what aging in C. elegans is in a fundamental sense. This will involve reference to some new approaches, questions and ideas, including the following. How does IIS cause age-related diseases, and how do these cause death? Are the same pathophysiological principles operative in the development of age-related diseases in C. elegans and mammals? Does IIS accelerate aging by promoting futile run-on of biological programmes as proposed by the Williams Blagosklonny theory [1,2], rather than through effects on molecular damage and somatic maintenance? Does IIS promote semelparous reproductive death in C. elegans, similar to that seen in Pacific salmon? And: could earlier death in post-reproductive C. elegans have evolved to promote inclusive fitness? [3] 1. Ezcurra M, et al. 2018 'C. elegans eats its own intestine to make yolk leading to multiple senescent pathologies.' Curr. Biol. 28: 2544. 2. Wang H, et al. 2018 'A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans.' NPJ Aging Mech. Dis. 4: 6. 3. Lohr JN, et al. 2019 'Does senescence promote fitness in Caenorhabditis elegans by causing death?' Ageing Res. Rev. 50: 58.
-
[
Nature,
2003]
Understanding how we grow old is a long-sought goal. A new large-scale study of gene expression in worms allows us to glimpse the complex biochemistry of lifespan.
-
[
SEB Exp Biol Ser,
2009]
-
[
Biogerontology,
2000]
In the developing field of biological gerontology, rapid advances have recently been made in the genetics of ageing in the nematode Caenorhabditis elegans. The aim of this work is to develop an understanding of the general mechanisms determining the ageing process. Within the last decade the prospect of actually achieving this somewhat hubristic aim has begun to look startlingly real. In this context, knowledge of every aspect of the biology of ageing in nematodes is of added interest. Here the patterns of ageing observed among parasitic and free-living nematodes are surveyed and compared. Like insects, nematode species exhibit enormous differences in the rate of ageing, with maximum life spans varying over more than a 1000-fold range, from three days in free-living Rhabdias bufonis adults, to at least 15 years in the filarial parasite Loa loa. The possible evolutionary and mechanistic causes of such differences in ageing are discussed.
-
[
Aging Cell,
2002]
A major challenge in current research into aging using model organisms is to establish whether different treatment resulting in slowed aging involve common or distinct mechanisms. Such treatments include gene mutation, dietary restriction (DR), and manipulation of reproduction, gonadal signals and temperature. The principal method used to determine whether these treatments act through common mechanisms is to compare the magnitude of the effect on aging of each treatment separately with that when two are applied simultaneously. In this discussion we identify five types of methodological shortcomings that have marred such studies. These are (1) submaximal lifespan-extension by individual treatments, e.g. as a result of the use of hypomorphic rather than null alleles; (2) effects of a single treatment on survival through more than one mechanism, e.g. pleiotropic effects of lifespans mutants; (3) the difficulty of interpreting the magnitude of increases in lifespan in double treatments, and failure to measure and model age-specific mortality rates; (4) the non-specific effects of life extension suppressors; and (5) the possible occurrence of artefactual mutant interactions. When considered in the light of these problems, the conclusions of a number of recent lifespan interaction studies appear questionable. We suggest six rules for avoiding the pitfalls that can beset interaction studies.
-
[
Cell Cycle,
2009]
The oxidative damage theory of aging once seemed almost proven. Yet recently the buzzards have been assembling in the blue skies above it. New challenges to the theory from work using nematode worms seem set to bring them down to peck at its bones. But is the theory really dead, or does it just need to be modified?
-
[
Curr Opin Genet Dev,
2001]
Although the underlying mechanisms of ageing are not understood, it is known that the longevity of the nematode Caenorhabditis elegans is modulated by an insulin/IGF-signalling pathway. The focus now is on how this pathway is regulated, how it controls nematode ageing, and how this relates to the ageing process in higher animals.
-
[
Front Cell Dev Biol,
2021]
In some species of salmon, reproductive maturity triggers the development of massive pathology resulting from reproductive effort, leading to rapid post-reproductive death. Such reproductive death, which occurs in many semelparous organisms (with a single bout of reproduction), can be prevented by blocking reproductive maturation, and this can increase lifespan dramatically. Reproductive death is often viewed as distinct from senescence in iteroparous organisms (with multiple bouts of reproduction) such as humans. Here we review the evidence that reproductive death occurs in <i>C. elegans</i> and discuss what this means for its use as a model organism to study aging. Inhibiting insulin/IGF-1 signaling and germline removal suppresses reproductive death and greatly extends lifespan in <i>C. elegans</i>, but can also extend lifespan to a small extent in iteroparous organisms. We argue that mechanisms of senescence operative in reproductive death exist in a less catastrophic form in iteroparous organisms, particularly those that involve costly resource reallocation, and exhibit endocrine-regulated plasticity. Thus, mechanisms of senescence in semelparous organisms (including plants) and iteroparous ones form an etiological continuum. Therefore understanding mechanisms of reproductive death in <i>C. elegans</i> can teach us about some mechanisms of senescence that are operative in iteroparous organisms.
-
[
Mechanisms of Ageing & Development,
2005]
Our recent survey of genes regulated by insulin/IGF-1 signaling (IIS) in Caenorhabditis elegans suggests a role for a number of gene classes in longevity assurance. Based on these findings, we propose a model for the biochemistry of longevity assurance and ageing, which is as follows. Ageing results from molecular damage from highly diverse endobiotic toxins. These are stochastic by-products of diverse metabolic processes, of which reactive oxygen species (ROS) are likely to be only one component. Our microarray analysis suggests a major role in longevity assurance of the phase 1, phase 2 detoxification system involving cytochrome P450 (CYP), short-chain dehydrogenase/ reductase (SDR) and UDP-glucuronosyltransferase (UGT) enzymes. Unlike superoxide and hydrogen peroxide detoxification, this system is energetically costly, and requires the excretion from the cell of its products. Given such costs, its activity may be selected against, as predicted by the disposable soma theory. CYP and UGT enzymes target lipophilic molecular species; insufficient activity of this system is consistent with age-pigment (lipofuscin) accumulation during ageing. We suggest that IIS-regulated longevity assurance involves: (a) energetically costly detoxification and excretion of molecular rubbish, and (b) conservation of existing proteins via molecular chaperones. Given the emphasis in this theory on investment in cellular waste disposal, and on protein conservation, we have dubbed it the green
-
[
J Biol Chem,
1995]
A full-length mRNA encoding a secreted 26-kDa antigen of infective larvae of the ascarid nematode parasite Toxocara canis has been identified. This was characterized as a 1,082-base pair clone highly abundant (0.8-1.9%) in cDNA prepared from infective stage larvae but absent from cDNA from adult male worms. Sequence analysis revealed an open reading frame corresponding to a hydrophilic 263-amino acid residue polypeptide with a 20-residue N-terminal signal peptide, indicating that it is secreted. The 5' end of the cDNA was isolated by polymerase chain reaction using a primer containing the nematode-spliced leader sequence, SL1, showing that the mRNA is trans-spliced. The molecular mass of the putative protein with the signal peptide removed is 26.01 kDa, and antibody to the recombinant protein expressed in bacterial vectors reacts with a similarly sized protein in T. canis excretory/secretory (TES) products. An identical sequence was obtained from a genomic clone isolated by expression screening with mouse antibody to TES. The 72 amino acid residues adjacent to the signal peptide form two homologous 36-residue motifs containing 6 cysteine residues; this motif is found also in the T. canis-secreted glycoprotein TES-120 and in genes of Caenorhabditis elegans. Sequence data base searches revealed significant similarity to 7 other sequences in a newly recognized gene family of phosphatidylethanolamine-binding proteins that includes yeast, Drosophila, rat, bovine, simian, and human genes and a representative from the filarial nematode Onchocerca volvulus. Assays with the T. canis recombinant 26-kDa protein expressed as a fusion with maltose-binding protein have confirmed phosphatidylethanolamine-binding specificity for this novel product.