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Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice
Stefano Squarzoni1,2, Elisa Schena1,2, Patrizia Sabatelli1,2
1CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, Bologna, Italy.
Insights
Tocilizumab, an interleukin-6 inhibitor, reverses aging signs in Hutchinson-Gilford progeria syndrome (HGPS) models. This study highlights its potential for treating HGPS and other age-related disorders.
Area of Science:
- Cellular and Molecular Biology
- Genetics
- Immunology
Background:
- Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder causing rapid premature aging.
- HGPS is characterized by tissue deterioration and cardiovascular issues, with elevated interleukin-6 (IL-6) levels observed.
- IL-6 is an inflammatory cytokine implicated in aging processes.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting interleukin-6 (IL-6) activity in Hutchinson-Gilford progeria syndrome (HGPS).
- To evaluate the efficacy of tocilizumab, an IL-6 receptor-blocking antibody, in preclinical models of HGPS.
Main Methods:
- Utilized HGPS patient-derived fibroblasts and LmnaG609G/G609G progeroid mouse models.
- Administered tocilizumab to counteract IL-6 activity.
- Assessed progerin accumulation, nuclear envelope and chromatin structure, DNA damage response, and various physiological parameters in vivo.
Main Results:
- Tocilizumab treatment reduced progerin accumulation and corrected nuclear abnormalities in HGPS fibroblasts.
- The antibody attenuated the hyperactivated DNA damage response in cellular models.
- In vivo, tocilizumab mitigated aortic lesions, adipose tissue dystrophy, and delayed onset of lipodystrophy and kyphosis in progeroid mice.
- Tocilizumab administration improved quality of life and prevented motor impairment in the mouse model.
Conclusions:
- Tocilizumab effectively counteracts progeroid features in cellular and animal models of HGPS.
- Inhibition of IL-6 signaling presents a promising therapeutic strategy for HGPS.
- This approach may hold potential for treating other age-related conditions.
Abstract:
Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G/G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders.
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