Prevention of accelerated presbycusis by bone marrow transplantation in senescence-accelerated mice

Abstract

Summary:A substrain of the senescence-accelerated mouse (SAM), the SAMP1 mouse, is an animal model for accelerated senescence including the age-related acceleration of both immunological dysfunction and hearing loss caused by the impairment of spiral ganglion cells. In the present study, we examine whether the accelerated presbycusis can be prevented by allogeneic BMT. Young SAMP1 (H-2 k ) mice were irradiated with 9 Gy and then reconstituted with bone marrow cells from normal BALB/c (H-2 d ) mice. Allogeneic BMT was found to prevent the development of immunological dysfunction, hearing loss, and apoptosis of spinal ganglion cells in SAMP1 mice. These findings indicate that some types of accelerated presbycusis do not result from defects in the cochlea, but do from defects in the hematopoietic stem cells (HSC) and immunocompetent cells derived from the HSC. If this is the case, either allogeneic BMT, which replaces abnormal HSC with normal HSC and reconstructs a normal immune system in the recipients, or autologous BMT using genetically modified bone marrow cells, could become a new strategy for the treatment of presbycusis. Bone Marrow Transplantation (2001) 28, 323-328. Keywords: presbycusis; spiral ganglion cell; bone marrow transplantation; T lymphocyte; apoptosis There has been no strategy for the prevention and treatment of presbycusis. There is a widespread presumption based on clinical observations that presbycusis is an inherited disorder, and that genetic factors may influence both the rate and severity of the hearing loss. 1,2 However, the genetic factors are still unclear, since more than one pathologic process may be acting upon the auditory system, 1 and environmental factors are also involved. 3 Among animal models of presbycusis, the SAMP1 mouse is most suitable by virtue of its progressive hearing loss with an onset at an early age, as well as accelerated senescence in an inherited pattern. 4,5 Molecular studies, such as transfer experiments of the Akv-1 gene 4 and apoA-II gene, 6 are in progress. Age-accelerated somatic mutations were also found in the hypoxanthine phosphoribosyl transferase (Hprt) locus of splenic lymphocytes. 7 This mouse strain shows an early occurrence of accelerated dysfunctions of immunocompetent cells, particularly T cells, 4,8 followed by accelerated hearing impairment, 5 the loss of physical activity, alopecia, periophthalmic lesions, and increased lordokyphosis of the spine, as well as spontaneous age-associated amyloidosis and shortened lifespan. 9,10 Early production of autoantibodies against DNA, thymocytes and collagen type II and the early deposition of immune complexes in the glomeruli of the kidney have been demonstrated in these mice. 11 Since age-related changes in the immune system appear relatively early in life, it is suggested that immune impairment may be a cause of age-related disease. 4 We have previously shown that the dysfunctions of immunocompetent cells, but not abnormalities in the cochlea, cause the development of autoimmune sensori-neural hearin...

The Complexity of Age-Related Hearing Impairment: Contributing Environmental and Genetic Factors

“…This was shown in a study using SAMP1 mice, a model for accelerated senescence, which suffer from hearing impairment and a decreased immune function. In a first study, the transplantation of bone marrow of BALB/c mice into SAMP1 mice prevented the development of immunological dysfunction and hearing loss, indicating that some types of accelerated ARHI are not caused by effects in the cochlea, but are due to hematopoietic stem cell defects and failing immunocompetent cells derived from these stem cells [Iwai et al, 2001]. The authors could rule out an autoimmune mechanism as causative factor.…”

Effect on lifespan of high yield non-myeloablating transplantation of bone marrow from young to old mice

“…These findings may explain the previously found, and not enough accounted for, effectiveness of bone marrow transplantation (BMT) in treating not only hematology diseases (Fanconi anemia; Gluckman et al, 1995) but also such systemic diseases as mucopolysaccharidosis and senile hearing impairment (Birkenmeier et al, 1991; Iwai et al, 2001; Corti et al, 2004; Willenbring et al, 2004). Mucopolysaccharidosis is caused by a deficiency in enzymes required for degradation of glucosamines that are accumulated in lysosomes of many organs, thereby leading to dysfunction and reduction of lifespan.…”

Bone marrow‐derived cells that home to acoustic deafened cochlea preserved their hematopoietic identity

“…Yoshida and coworkers (2007) made use of HSCs to prevent hair cell death and to ameliorate hearing impairment after transient cochlea ischemia. Iwai and coworkers (2001) employed bone marrow transplantation (BMT) to replace abnormal HSCs with normal HSCs to treat presbycusis. MSCs from the bone marrow have been shown to differentiate into inner ear hair cells in vitro (Jeon et al,2007), and transplantation aided cochlea fibrocyte recovery in a deafened rat model (Kamiya et al,2007).…”