Donohue Syndrome

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans, Drosophila, and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans , Drosophila , and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension xwas abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

Captopril and acn-1 control aging. By demonstrating they regulate dauer formation and interact with daf genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.