Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin

Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the GM2 gangliosidoses. One strategy for treating this and related diseases is substrate deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease.

Chronic elevation of plasma thioredoxin: Inhibition of chemotaxis and curtailment of life expectancy in AIDS

Thioredoxin (Trx) is an intracellular redox protein with extracellular cytokine-like and chemokine-like activities. We show here that, although plasma Trx levels are unrelated to survival of HIV-infected individuals with CD4 cell counts above 200/μl blood, survival is significantly impaired (P = 0.003) when plasma Trx is chronically elevated in HIV-infected subjects with CD4 T cell counts below this level (i.e., with Centers for Disease Control (CDC)-defined AIDS). Relevant to the mechanism potentially underlying this finding, we also present data from experimental studies in mice showing that elevated plasma Trx efficiently blocks lipopolysaccharide (LPS)-induced chemotaxis, an innate immune mechanism that is particularly crucial when adaptive immunity is compromised. Thus, we propose that elevated plasma Trx in HIV-infected individuals with low CD4 T cell counts directly impairs survival by blocking pathogen-induced chemotaxis, effectively eliminating the last (innate) barrier against establishment of opportunistic and other infections in these immunodeficient individuals.

Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress.

We have discovered that three longevity mutants of the nematode Caenorhabditis elegans also exhibit increased intrinsic thermotolerance (Itt) as young adults. Mutation of the age-1 gene causes not only 65% longer life expectancy but also Itt. The Itt phenotype cosegregates with age-1. Long-lived spe-26 and daf-2 mutants also exhibit Itt. We investigated the relationship between increased thermotolerance and increased life-span by developing conditions for environmental induction of thermotolerance. Such pretreatments at sublethal temperatures induce significant increases in thermotolerance and small but statistically highly significant increases in life expectancy, consistent with a causal connection between these two traits. Thus, when an animal's resistance to stress is increased, by either genetic or environmental manipulation, we also observe an increase in life expectancy. These results suggest that ability to respond to stress limits the life expectancy of C. elegans and might do so in other metazoa as well.

Economic change, crime, and mortality crisis in Russia: regional analysis

Objective: To identify which aspects of socioeconomic change were associated with the steep decline in life expectancy in Russia between 1990 and 1994.

Lifespan depends on month of birth

Month of birth influences adult life expectancy at ages 50+. Why? In two countries of the Northern Hemisphere–Austria and Denmark–people born in autumn (October–December) live longer than those born in spring (April–June). Data for Australia show that, in the Southern Hemisphere, the pattern is shifted by half a year. The lifespan pattern of British immigrants to Australia is similar to that of Austrians and Danes and significantly different from that of Australians. These findings are based on population data with more than a million observations and little or no selectivity. The differences in lifespan are independent of the seasonal distribution of deaths and the social differences in the seasonal distribution of births. In the Northern Hemisphere, the excess mortality in the first year of life of infants born in spring does not support the explanation of selective infant survival. Instead, remaining life expectancy at age 50 appears to depend on factors that arise in utero or early in infancy and that increase susceptibility to diseases later in life. This result is consistent with the finding that, at the turn of the last century, infants born in autumn had higher birth weights than those born in other seasons. Furthermore, differences in adult lifespan by month of birth decrease over time and are significantly smaller in more recent cohorts, which benefited from substantial improvements in maternal and infant health.

Mice lacking DNA topoisomerase IIIβ develop to maturity but show a reduced mean lifespan

Targeted gene disruption in the murine TOP3β gene-encoding DNA topoisomerase IIIβ was carried out. In contrast to the embryonic lethality of mutant mice lacking DNA topoisomerase IIIα, top3β−/− nulls are viable and grow to maturity with no apparent defects. Mice lacking DNA topoisomerase IIIβ have a shorter life expectancy than their wild-type littermates, however. The mean lifespan of the top3β−/− mice is about 15 months, whereas that of their wild-type littermates is longer than 2 years. Mortality of the top3β−/− nulls appears to correlate with lesions in multiple organs, including hypertrophy of the spleen and submandibular lymph nodes, glomerulonephritis, and perivascular infiltrates in various organs. Because the DNA topoisomerase III isozymes are likely to interact with helicases of the RecQ family, enzymes that include the determinants of human Bloom, Werner, and Rothmund–Thomson syndromes, the shortened lifespan of top3β−/− mice points to the possibility that the DNA topoisomerase III isozymes might be involved in the pathogenesis of progeroid syndromes caused by defective RecQ helicases.

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members

The development of Alzheimer's disease (AD) later in life may be reflective of environmental factors operating over the course of a lifetime. Educational and occupational attainments have been found to be protective against the development of the disease but participation in activities has received little attention. In a case-control study, we collected questionnaire data about 26 nonoccupational activities from ages 20 to 60. Participants included 193 people with probable or possible AD and 358 healthy control-group members. Activity patterns for intellectual, passive, and physical activities were classified by using an adaptation of a published scale in terms of “diversity” (total number of activities), “intensity” (hours per month), and “percentage intensity” (percentage of total activity hours devoted to each activity category). The control group was more active during midlife than the case group was for all three activity categories, even after controlling for age, gender, income adequacy, and education. The odds ratio for AD in those performing less than the mean value of activities was 3.85 (95% confidence interval: 2.65–5.58, P < 0.001). The increase in time devoted to intellectual activities from early adulthood (20–39) to middle adulthood (40–60) was associated with a significant decrease in the probability of membership in the case group. We conclude that diversity of activities and intensity of intellectual activities were reduced in patients with AD as compared with the control group. These findings may be because inactivity is a risk factor for the disease or because inactivity is a reflection of very early subclinical effects of the disease, or both.

Invariance and restriction toward a limited set of self-antigens characterize neonatal IgM antibody repertoires and prevail in autoreactive repertoires of healthy adults.

Analysis of the reactivity of IgM with self-antigens in tissues by a quantitative immunoblotting technique showed striking invariance among newborns in the human and in the mouse. The self-reactive repertoire of IgM of adults was also markedly conserved; it comprised most anti-self reactivities that prevailed among neonates. Multivariate analysis confirmed the homogeneity of IgM repertoires of neonates toward self- and non-self-antigens. Multivariate analysis discriminated between newborn and adult repertoires for reactivity with two of five sources of self-proteins and with non-self-antigens. Our observations support the concept that naturally activated B lymphocytes are selected early in development and throughout life for reactivity with a restricted set of self-antigens.