Abstract Background Aging process may result in immune modifications that lead to disruption of innate and acquired immunity mechanisms that may induce chronic-degenerative events. The heat shock proteins (Hsp), phylogeneticaly conserved among organisms, present as main function the ability of folding and refolding proteins, but they also are associated with chronic-degenerative disorders. Here were evaluated the role of M. leprae native Hsp65 (WT) and its point-mutated (K 409 A) on survival and anti-DNA and anti-Hsp65 antibody production of aged genetically selected mice for high (H III ) and low (L III ) antibody production; data from 120- and 270-days old mice (named “adult” or “aged”, respectively) were compared. Results WT Hsp65 administration induces reduction in the mean survival time of adult and aged female H III mice, this effect being stronger in aged individuals. Surprisingly, the native protein administration increased the survival of aged female L III when compared to K 409 A and control groups. No survival differences were observed in aged male mice after Hsp65 proteins inoculation. We observed increase in IgG1 anti-Hsp65 in WT and K 409 A aged H III female mice groups and no marked changes in the anti-DNA (adult and aged H III ) and anti-Hsp65 IgG1 or IgG2a isotypes production in adult H III female and aged male mice. L III male mice presented increased anti-DNA and anti-Hsp65 IgG2a isotype production after WT or K 409 A injection, and L III female groups showed no alterations. Conclusions The results revealed that the WT Hsp65 interferes with survival of aged H III female mice without involvement of a remarkable IgG1 and IgG2a anti-DNA and anti-Hsp65 antibodies production. The deleterious effects of Hsp65 on survival time in aged H III female mice could be linked to a gender-effect and are in agreement with those previously reported in lupus-prone mice.