Long recognized as the cell’s recycling depot, a new study has found lysosomes act as signaling hubs that coordinate metabolism and longevity by communicating signals across tissues.

According to a 2019 United Nations report, by 2050 the number of people in the world above 65 years will be over 1.5 billion. This underscores the need for a clear understanding of the elusive processes of aging and age-related health conditions.

Earlier studies have shown that changes in lysosomal activity play a role in aging-associated metabolic and neurodegenerative diseases. But the mechanisms that link lysosomal metabolism to coordinated aging across neural and metabolic systems, remain hazy.

The study (‘Lysosome lipid signaling from the periphery to neurons regulates longevity’) published in Nature Cell Biology shows roundworm (Caenorhabditis elegans) lysosomes break down stored fat molecules to produce messenger molecules that bolster communication among neurons, enabling cells throughout the organism to age synchronously.

Senior author of the study, Meng Wang, PhD, professor, chair on aging of molecular and human genetics, and an HHMI investigator at Baylor College of Medicine said: “[The study] helps us understand how longevity is regulated at a whole organism level.”

The authors noted, “We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signaling pathway in the nervous system to promote longevity.”

“It’s a very beautiful piece of work,” said Xiaochen Wang, PhD, a biophysicist at the Chinese Academy of Sciences (CAS) in Beijing who specializes in lysosomes and was one of the reviewers of the Nature Cell Biology article. Xiaochen Wang believes the work stands out because it was conducted in a living organism, rather than in cultured cells typically used to study lysosomes, and focuses on how one lysosomal molecule travels to the cell’s nucleus and acts as an anti-aging signal.

Lysosomes are tiny spherical sacs, ranging in size from 0.1 to 0.5 microns in diameter, bound by a lipid bilayer. They house hydrolytic enzymes that break down unwanted biomolecules or invading pathogens.

Senior author of the study, Meng Wang said, “Cells in different organs and tissues around the body send signals to one another constantly. When we are young, everything is connected and communicating, but as we age, some of these connections are lost and function declines.”

Meng Wang has spent the past seven years exploring links between longevity and lysosomal metabolites. She is motivated by the longevity that runs in her family. Her paternal and maternal grandmothers lived to 100 and 95 years, respectively. “Neither was ill, and why they died remains a mystery. It makes me feel like there’s some secret to longevity, and if we can study this, maybe we can use the knowledge and apply it to everyone,” said Wang.

Xiaochen Wang said, “Scientists have known for more than 50 years that proteins, lipids, and other molecules tend to accumulate in cells that are old, but only now are people paying more attention to these pieces of data.”

Lysosomes, being the dumping grounds for cellular waste products, are drawing the attention of scientists who suspect a link between aging and lysosomal function. Studies in the past decade, have shown cells broadcast their biological state, such as glucose and stress levels, using lysosomal signals. In a 2015 paper in Science, Meng Wang’s group discovered lysosomes in C. elegans produce anti-aging signals.

In the current study, Marzia Savini, a PhD student in Meng Wang’s group discovered that when lysosomes produce a specific polyunsaturated fatty acid (dihomo-γ-linoleic acid), it triggers a chain of cellular messages that extend the worm’s lifespan. The signal molecule was generated in fat tissues but was detected by neurons elsewhere in the worms, indicating lysosomal signals coordinate longevity across cells in different tissues.

In this study, the team identified two lipid chaperones that mediate the signaling role of lysosomes and act in parallel to regulate longevity. LBP-8 facilitates retrograde signaling from the lysosome to the nucleus while LBP-3 promotes endocrine signaling from fat cells to neurons. The investigators demonstrated that LBP-3 binds to dihomo-γ-linolenic acid, and acts through a nuclear receptor (NHR-49) and a neuropeptide (NLP-11) in neurons to extend the worm’s lifespan.

Meng Wang and her team continue to hunt for molecules lysosomes produce that may act as anti-aging signals. “There’s still so much to uncover, such as figuring out when the molecules begin acting as signals, how they regulate aging, and how that function withers with age. The goal is not to have everyone live for centuries but for people to spend their last years healthy, active, and independent—just like my grandmothers. I’m passionate to know how people and organisms sustain health with time,” said Meng Wang.

This study arose from a collaboration among the Baylor College of Medicine, Howard Hughes Medical Institute at Baylor, University of Texas Health Science Center at Houston, University of California San Francisco, Emory University School of Medicine, Harvard T.H. Chan School of Public Health at Boston, and the Texas A&M University, Houston.

The work was funded by grants from the National Institutes of Health (NIH), the Welch Foundation, and the Howard Hughes Medical Institute (HHMI).

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