Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish.

Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.

Telomeres in aging and disease: lessons from zebrafish.

Age is the highest risk factor for some of the most prevalent human diseases, including cancer. Telomere shortening is thought to play a central role in the aging process in humans. The link between telomeres and aging is highlighted by the fact that genetic diseases causing telomerase deficiency are associated with premature aging and increased risk of cancer. For the last two decades, this link has been mostly investigated using mice that have long telomeres. However, zebrafish has recently emerged as a powerful and complementary model system to study telomere biology. Zebrafish possess human-like short telomeres that progressively decline with age, reaching lengths in old age that are observed when telomerase is mutated. The extensive characterization of its well-conserved molecular and cellular physiology makes this vertebrate an excellent model to unravel the underlying relationship between telomere shortening, tissue regeneration, aging and disease. In this Review, we explore the advantages of using zebrafish in telomere research and discuss the primary discoveries made in this model that have contributed to expanding our knowledge of how telomere attrition contributes to cellular senescence, organ dysfunction and disease.

Mitochondrial quality control and Parkinson's disease: a pathway unfolds.

Recent findings from genetic studies suggest that defective mitochondrial quality control may play an important role in the development of Parkinson's disease (PD). Such defects may result in the impairment of neuronal mitochondria, which leads to both synaptic dysfunction and cell death and results in neurodegeneration. Here, we review state-of-the-art knowledge of how pathways affecting mitochondrial quality control might contribute to PD, with a particular emphasis on the molecular mechanisms employed by PTEN-induced putative kinase 1 (PINK1), HtrA2 and Parkin to regulate mitochondrial quality control.

Mitochondrial quality control and neurological disease: an emerging connection.

The human brain is a highly complex organ with remarkable energy demands. Although it represents only 2% of the total body weight, it accounts for 20% of all oxygen consumption, reflecting its high rate of metabolic activity. Mitochondria have a crucial role in the supply of energy to the brain. Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders. Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components. Here, we review some of the most recent advances in the understanding of mitochondrial stress-control pathways, with a particular focus on how defects in such pathways might contribute to neurodegenerative disease.