Abstract
Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial DNA, and telomeres in the reduced life span of Cbs−/− mice. We found that senescence-related p21, Pai-1, Mcp1, and Il-6 mRNAs were significantly upregulated (2–10-fold) in liver, while p21 was upregulated in the brain of Cbs−/− mice (n = 20) compared with control Cbs+/− siblings (n = 20) in a sex- and age-dependent manner. Telomere length in blood (n = 80), liver (n = 40), and brain (n = 40) was not affected by the Cbs−/− genotype, but varied with sex and/or age. Levels of mitochondrial DNA tended to be reduced in livers, but not brains and blood, of Cbs−/− females (n = 20–40). The Cbs−/− genotype significantly reduced Tert mRNA expression in brain, but not liver, in a sex- and age-dependent manner. Multiple regression analysis showed that the senescence-related liver (but not brain) mRNAs and liver (but not brain or blood) mitochondrial DNA were associated with the Cbs genotype. In contrast, telomere length in blood, brain, and liver was not associated with the Cbs genotype or hyperhomocysteinemia, but was associated with sex (in brain and liver) and age (in brain and blood). Taken together, these findings suggest that the changes in senescence marker expression and mtDNA levels, but not telomere shortening, could account for the reduced life span of Cbs−/− mice.
Highlights
Cellular senescence irreversibly arrests proliferation and is an important contributor to aging and age-related disease [1]
Tg-I278T Cbs−/− mice have severe hyperhomocysteinemia (HHcy), a 25% shorter life span (613 vs. 821 days) [27], and are characterized by a thin, smooth, shiny tail [29] and a reduced body weight [29]
We examined a possible involvement of telomere shortening, Mitochondrial DNA (mtDNA) copy number, and accelerated senescence in the reduced life span of Cbs−/− mice
Summary
Cellular senescence irreversibly arrests proliferation and is an important contributor to aging and age-related disease [1]. The telomere sequence is more sensitive to damage than non-telomeric DNA, and its length progressively shortens with age during somatic cell division. Short telomeres are a feature associated with cellular senescence and death. Short telomeres are usually found in a variety of human diseases that lead to premature death [9]. Recent findings in a variety of bird and mammalian species show that the telomere shortening rate, but not the telomere length alone, is a predictor of species life span [11]. Several genetic loci, including five known to be involved in telomere biology, are associated with telomere length and with increased risk of age-related diseases in humans [12]. Shorter telomeres are found in men vs. women, in older vs. younger individuals, and in Caucasian vs. other races [13]
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