Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

Abstract

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.

A genetically encoded, pH-sensitive mTFP1 biosensor for probing lysosomal pH

“…In addition, the nematode is highly amenable to genetic manipulation, has a short lifespan, and can be easily imaged through its transparent body wall (Apfeld & Alper, 2018; Kao et al, 2011). In recent years, studies on lysosomal biology have taken advantage of these features in C. elegans to determine key roles for the lysosome in stem cell maintenance (Bohnert & Kenyon, 2017) and aging-associated phenomena (Sun et al, 2020). Thus, we adapted FIRE-pHLy for study in C. elegans .…”

“…In contrast, loss of lysosomal acidity is observed in aging. Yeast vacuoles (metazoan homolog of lysosomes) and C. elegans lysosomes lose their acidity with increasing age (Baxi et al, 2017; Hughes & Gottschling, 2012; Sun et al, 2020), but can be rescued with caloric restriction that upregulates V-ATPase activity (Hughes & Gottschling, 2012). Additionally, neuronal health is highly regulated by lysosomal function, as demonstrated by insights from human genetics that link lysosomal dysfunction to a wide range of neurological diseases (Malik et al, 2019; Platt et al, 2012).…”

Tubular lysosomes harbor active ion gradients and poise macrophages for phagocytosis

“…We therefore tested whether MMP9 expression increased upon Tudor treatment, since MMP9 transcription can be stimulated by either NF-κB or Nrf2. The former can be activated upon immunostimulation (73,74) while the latter is activated during cell starvation or oxidative stress (11,75). Pharmacological inhibition of NF-κB and Nrf2 by JSH-23 and ML385 respectively .…”

“…Although lysosomes are generally vesicular, they can form reticulated tubules that are several microns long (4)(5)(6). New roles are rapidly emerging for tubular lysosomes (5,(7)(8)(9)(10)(11). In dendritic cells, tubular lysosomes fuse with the cell membrane leading to antigen presentation (12)(13)(14).…”

“…Tubular lysosomes are generally observed when the cell is undergoing either autophagy or immune activation (4,7,9,11,16,17,19). While tubulation per se occurs universally along microtubules, the biochemistry within tubular lysosomes in different contexts varies remarkably.…”