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Increased resistance of lipofuscin-loaded prematurely senescent fibroblasts to starvation-induced programmed cell death

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Abstract

Alterations of cellular structures often found in ageing cells is mainly the result of production of reactive oxygen species and a consequence of aerobic life. Both oxidative stress and decreased degradative capacity of lysosomal system cause accumulation of intralysosomal age-related pigment called lipofuscin. To investigate the influence of lipofuscin on cell function, we compared survival of lipofuscin-loaded and control human fibroblasts following complete starvation induced by exposure to phosphate-buffered saline (PBS). Starving of control fibroblasts resulted in lysosomal alkalinisation, relocation of cathepsin D to the cytosol, caspase-3 activation and, finally, cell death, which became evident 72 h after the start of exposure to PBS. Increase of lysosomal pH was significantly less prominent in lipofuscin-loaded cells than in controls and was accompanied neither by leakage of cathepsin D nor by caspase-3 activation even 96 h after the initiation of starvation. Suppression of autophagy by 3-methyladenine (3-MA) accelerated cell death, while inhibition of cathepsin D delayed it, implying an important role of autophagy in cell survival during starvation and showing the involvement of lysosomes in starvation-induced cell death. Disturbed apoptotic response found in lipofuscin-loaded cells can be interpreted as an example of hormesis—an adaptation to low doses of otherwise harmful agents, in this case of lipofuscin, which has a protective effect at moderate amounts but becomes toxic at large quantities.

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Acknowledgements

This study was financially supported by Lions Research Foundation and by grant from the Medical Branch of the Swedish Research Council (Vetenskapsrådet).

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Authors and Affiliations

  1. Faculty of Health Sciences, Division of Experimental Pathology, Department of Neuroscience and Locomotion, Linköping University, SE-58185, Linköping, Sweden

    Yuri Stroikin, Uno Johansson, Sofia Asplund & Karin Öllinger

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  1. Yuri Stroikin
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  2. Uno Johansson
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  3. Sofia Asplund
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Correspondence to Yuri Stroikin.

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Stroikin, Y., Johansson, U., Asplund, S. et al. Increased resistance of lipofuscin-loaded prematurely senescent fibroblasts to starvation-induced programmed cell death. Biogerontology 8, 43–53 (2007). https://doi.org/10.1007/s10522-006-9029-7

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