Lysosomal polarity increases with aging as revealed by a lysosome-targetable near-infrared fluorescent probe

Cellular senescence, the major inducer of aging contributing to chronic diseases and age-related dysfunctions, is characterized by remarkable variations in the morphology and functionality of cellular organelles. Increases in lysosomal number, pH and size constitute the most characteristic variations observed with senescence, in which increased pH can further impact the microenvironment of lysosomes. These senescence-related alterations in lysosomes causally induce changes in lysosomal polarity. However, the relationship between lysosomal polarity and senescence remains a “grey area”. To this end, we presented a series of curcumin-based polarity fluorescent probes, among which KSLP1 is a near-infrared lysosome-targeting probe that can monitor lysosomal polarity with high sensitivity without interference from other micro-environmental factors. Utilizing KSLP1, we investigated variations in polarity in drug-induced senescent cells and senescent MRC5 cells, and we discovered, for the first time, that lysosomal polarity increased in senescent cells and proposed a mechanism for variations in lysosomal polarity. Moreover, the polarity of C. elegans was monitored from days 2 to 10 of adulthood, and the results indicated that the intrinsic polarity in C. elegans increased with aging. These results demonstrated that lysosomal polarity increases with senescence, providing insight into the relationship between lysosomal polarity and the aging process.