Longevity of SLE-prone mice increased by dietary 2-mercaptoethanol via a mechanism imprinted within the first 28 days of life

Abstract

In the preceding report, moderately lived-mice fed dietary 2-mercaptoethanol (2-Me) had their life extended, whereas long-lived mice were found to have the quality of life improved, but not extended, and did not develop high fat-diet obesity. In the present report, alteration of longevity of mice prone to develop spontaneous, systemic lupus erythematosus (SLE) by dietary 2-Me was determined. NZB, NZW, (NZW x NZB) F1-hybrid, BXSB/MpJ, BXSB-Yaa+/J, MRL/MpJ and MRL/MpJ-Faslpr mice received drinking water, without or with 2-Me at concentrations of 10-3 or 10-2 M. Therapeutic benefit was assessed by changes in longevity. The median survival of MRL/MpJ males was increased from 443 to 615 days and those of (NZW x NZB) F1 and NZB males and females were increased approximately 2-fold. The most unexpected finding was that longevity of F1 males was significantly extended irrespective of whether dietary exposure to 2-Me was initiated at 28 days of age, at 50 days of age, or initiated during gestation (and then terminated at weaning--28 days of age). Survival of F1-hybrids in which treatment was initiated in utero or at 28 days of age was not significantly different, whereas if initiation was delayed until 50 days of age, survival was >200 days shorter. Survival of male MRL/MpJ-Fas lpr and BXSB/MpJ (Yaa-), two strains with genetically controlled accelerated SLE, was not altered by 2-Me when started at 50 days. Various alternatives are discussed regarding potential long-lasting mechanisms imprinted early in life. Even though present day treatments of rodent SLE are generally aimed at controlling specific immunological events, with or without survival benefits, or are procedures presently unsuitable for therapeutic use in humans, the findings presented herein seem worthy of clinical evaluation.

Acknowlededgements

A special thank you to Dr. Ellen Heber-Katz for excellent suggestions during the preparation of the manuscript. NIH Grants R01CA023678 and R01AI019643 funded this research, in part.

Figures and Tables

Figure 1 Longevity of (NZW × NZB) F₁-hybrid male and female mice exposed to normal, 10⁻³ M or 10⁻² M 2-Me drinking water. (A) Females. Treatment started at 28 days of age. Nontreated water shown in black (n = 9), 10⁻³ M 2-Me water in red (n = 8) and 10⁻² M 2-Me water in blue (n = 11). (B) Males. Treatment started at 28 days of age. Control (n = 15), 10⁻³ M 2-Me (n = 9), 10⁻² M 2-Me (n = 11). (C) Males. Grandparents and parents on 10⁻³ M 2-Me their entire lives. At 28 days of age, water of offspring of these parents/grandpaarents was switched to: nontreated water (n = 6), 10⁻² M 2-Me (n = 7), or continued on 10⁻³ M 2-Me (n = 10) for the remainder of their lives. Animals with solid tumors or ascites are designated by +.

Figure 2 Longevity of NZB and NZW mice not treated or treated with 10⁻³ or 10⁻² M 2-Me. (A and B) Females. (C and D) Males. Treatment started at 28 days of age for control shown in black, 10⁻³ M 2-Me in red and 10⁻² M 2-Me in blue. Animals with solid tumors or ascites are designated by +.

Figure 3 Longevity of MRL/MpJ (shown in black) and MRL/MpJ-Fas^lpr/J (shown in red) males not treated (open triangles) or treated with 10⁻² M 2-Me starting at 50 days (closed triangles). Five mice per treatment.

Figure 4 Longevity of BXSB-Yaa⁺/J (shown in black) and BXSB/MpJ (shown in red) males not treated (open triangles) or treated with 10⁻² M 2-Me starting at 50 days (closed triangles). Five mice per treatment.

Figure 5 Survival of (NZW × NZB) F₁ males started on 10⁻³ M 2-Me at different ages. Not treated shown in black (n = 15). Started in utero shown in blue, (n = 10). Started at 28 days of age shown in red (n = 9) and started at 50 days shown in green (n = 6).

Table 1 Median life span of 2-Me-treated/non-treated strains of mice

Table 2 Body weight and average daily intake of food, water and 2-Me by male (NZW × NZB) F₁ and C57BL10 mice at 210 days of age