What do we mean by “aging”? Questions and perspectives revealed by studies in Drosophila

Wodrich, Andrew P.K.; Scott, Andrew W.; Giniger, Edward

doi:10.1016/j.mad.2023.111839

“…Aging is best described as a progressive increase in the probability of death for an individual with the passage of time [72,73]. It is well established that there is a gradual decline of autophagy leading to loss of proteostasis with age, and hence, loss of autophagy is often considered one of the causal factors of aging; decreasing proteostasis is systemically controlled among tissues, hence suggesting a cell non-autonomous regulation of autophagy [74][75][76][77][78][79][80].…”

Section: Non-autonomously Regulated Autophagy In Agingmentioning

confidence: 99%

Illuminating Intercellular Autophagy: A Comprehensive Review of Cell Non-Autonomous Autophagy

Selarka,

Shravage

2024

Preprint

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Macro-autophagy (autophagy hereafter) is an evolutionarily conserved cellular process that has long been recognized as an intracellular mechanism for maintaining cellular homeostasis. It involves the formation of a membraned structure called the autophagosome, which carries cargo that includes toxic protein aggregates and dysfunctional organelles to the lysosome for degradation and recycling. Autophagy is primarily considered and studied as a cell-autonomous mechanism. However, recent studies have illuminated an underappreciated facet of autophagy, i.e., non-autonomously regulated autophagy. Non- autonomously regulated autophagy involves the degradation of autophagic components, including organelles, cargo, and signaling molecules, and is induced in neighboring cells by signals from primary adjacent or distant cells/tissues/organs. This review provides insight into the complex molecular mechanisms governing non-autonomously regulated autophagy, highlighting the dynamic interplay between cells within tissue/organ or distinct cell types in different tissues/organs. Emphasis is placed on modes of intercellular communication that include secreted molecules, including microRNAs, and their regulatory roles in orchestrating this phenomenon. Furthermore, we explore the multidimensional roles of non-autonomously regulated autophagy in various physiological contexts, spanning tissue development and aging, as well as its importance in diverse pathological conditions, including cancer and neurodegeneration. By studying the complexities of non-autonomously regulated autophagy, we hope to gain insights into the sophisticated intercellular dynamics within multicellular organisms, including mammals. These studies will uncover novel avenues for therapeutic intervention to modulate intercellular autophagic pathways in altered human physiology.

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“…Aging is best described as a progressive increase in the probability of death for an individual with the passage of time [71,72]. It is well established that there is a gradual decline of autophagy leading to loss of proteostasis with age, and hence, loss of autophagy is often considered one of the causal factors of aging; decreasing proteostasis is systemically controlled among tissues, hence suggesting a cell non-autonomous regulation of autophagy [73][74][75][76][77][78][79].…”

Section: Non-autonomously Regulated Autophagy In Agingmentioning

confidence: 99%

Illuminating Intercellular Autophagy: A Comprehensive Review of Cell Non-Autonomous Autophagy

Selarka,

Shravage

2024

Preprint

0

View full text Add to dashboard Cite

Macro-autophagy (autophagy hereafter) is an evolutionarily conserved cellular process that has long been recognized as an intracellular mechanism for maintaining cellular homeostasis. It involves the formation of a membraned structure called the autophagosome, which carries cargo that includes toxic protein aggregates and dysfunctional organelles to the lysosome for degradation and recycling. Autophagy is primarily considered and studied as a cell-autonomous mechanism. However, recent studies have illuminated an underappreciated facet of autophagy, i.e., non-autonomously regulated autophagy. Non- autonomously regulated autophagy involves the degradation of autophagic components, including organelles, cargo, and signaling molecules, and is induced in neighboring cells by signals from primary adjacent or distant cells/tissues/organs. This review provides insight into the complex molecular mechanisms governing non-autonomously regulated autophagy, highlighting the dynamic interplay between cells within tissue/organ or distinct cell types in different tissues/organs. Emphasis is placed on modes of intercellular communication that include secreted molecules, including microRNAs, and their regulatory roles in orchestrating this phenomenon. Furthermore, we explore the multidimensional roles of non-autonomously regulated autophagy in various physiological contexts, spanning tissue development and aging, as well as its importance in diverse pathological conditions, including cancer and neurodegeneration. By studying the complexities of non-autonomously regulated autophagy, we hope to gain insights into the sophisticated intercellular dynamics within multicellular organisms, including mammals. These studies will uncover novel avenues for therapeutic intervention to modulate intercellular autophagic pathways in altered human physiology.

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“…For example, inducing ROS production has been shown to extend lifespan in multiple species (Lee et al, 2010; Oka et al, 2015; Schroeder et al, 2013), while manipulations of antioxidant genes have surprisingly variable effects on organismal fitness despite altered levels of ROS (Page et al, 2010; Pérez et al, 2009; Ran et al, 2007; Van Raamsdonk & Hekimi, 2009). There remains no clear-cut answer to the question of whether ROS are detrimental by-products of metabolism or potentially beneficial signaling molecules, or whether either can be true, depending on the context (Wodrich et al, 2023). It also remains unclear whether the changes in redox state that occur in aging and neurodegeneration reflect a homeostatic response, contribute to dysfunction, or simply occur in parallel with the causative pathology.…”

Section: Introductionmentioning

confidence: 99%

MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN ADROSOPHILAMODEL OF NEURODEGENERATION

Wodrich,

Harris,

Giniger

2024

Preprint

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Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using a Drosophila model of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses, or whether they are simply covariates of pathology that do not alter viability. We find, surprisingly, that increasing mitochondrial H2O2 correlates with improved survival. We also find evidence that drugs that alter the mitochondrial glutathione redox potential modulate survival primarily through the compensatory effects they induce rather than through their direct effects on the final mitochondrial glutathione redox potential per se. We also find that the response to treatment with a redox-altering drug varies dramatically depending on the age at which the drug is administered, the duration of the treatment, and the genotype of the individual receiving the drug. These data have important implications for the design and interpretation of studies investigating the effect of redox state on health and disease as well as on efforts to modify the redox state to achieve therapeutic goals.

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What do we mean by “aging”? Questions and perspectives revealed by studies in Drosophila

Cited by 5 publications

References 249 publications

Illuminating Intercellular Autophagy: A Comprehensive Review of Cell Non-Autonomous Autophagy

Illuminating Intercellular Autophagy: A Comprehensive Review of Cell Non-Autonomous Autophagy

Illuminating Intercellular Autophagy: A Comprehensive Review of Cell Non-Autonomous Autophagy

MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN ADROSOPHILAMODEL OF NEURODEGENERATION

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