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Signals from adipose tissue prolong the life of nerve cells

Aging is a process of progressive cellular decline, which I discussed in detail in my book on neurodegeneration (chapter 2.1). Neuronal cell death is well studied at the cellular and molecular level. In particular, the cellular nucleus, but also mitochondria and lysosomes are of crucial importance.

Lysosomes, discovered by de Duve in 1959, play a central role in the aging process because they can metabolize almost all substrates, many of which accumulate in the cell over time (Fig. 1). Among the 60 lysosomal hydrolases are those that cleave sugar chains (polysaccharides), nucleic acids (DNA), and fats (lipids). Lysosomes are thus involved not only in protein homeostasis but also in lipid metabolism, as acid lipases release free fatty acids from triacylglycerols and cholesterol esters.

Fig. 1 A cell takes up various substances (yellow dots) from outside by endocytosis (after invagination of the plasma membrane), packs them into vesicles (endosomes) and distributes them. In addition, protein aggregates (green), as well as whole organelles (such as mitochondria, pink), are enclosed by intracellular membranes when needed. These processes are referred to as autophagy and mitophagy, respectively. Autophagosomes in turn fuse with lysosomes, which use cleaving enzymes to degrade their contents. This makes individual amino acids, glucose or lipids available again to cellular metabolism (but the vast majority of cytoplasmic proteins are degraded in the proteasome). Furthermore, vesicles are detached inwardly from the endosomal membrane (as in endocytosis). Several endosomes form multi-vesicular bodies (MVBs). Other substances are also released directly into the extracellular space by exocytosis or are discharged in the form of small vesicles (exosomes). Structures not drawn to scale; ER = endoplasmic reticulum; modified Fig. 2.3 from Klimaschewski L.P. , Parkinson's and Alzheimer's today. Springer, 2022.

A recent study by Meng Wang and colleagues published in Nature Cell Biology now presents a novel signaling pathway that identifies lysosomally formed fatty acids as signals between adipose and neural tissue. They promote lifespan, i.e. delay the aging process. The authors used the nematode Caenorhabditis elegans as a model. Although this worm is evolutionarily far away from humans (with only 385 nerve cells), it has been a recognized animal model of neurodegenerative and age-related changes in humans for many years.

The intestine of C. elegans produces LIPL-4, a lysosomal acid lipase. A distinctive feature of the worm is that the intestine functions as a peripheral fat store. LIPL-4 is upregulated during fasting and in a long-lived worm mutant with reduced insulin/IGF-1 signaling. In intestinal cells, this lipase induction activates a retrograde lipid signaling pathway from the lysosome to the nucleus to regulate transcription and mitochondrial metabolism, leading to increased lipolysis and lifespan.

Until now, the signaling function of lysosomes in inter-tissue communication was unknown. However, in this study, it has now been shown that LIPL-4-dependent lipolysis upregulates the so-called dihomo-γ-linolenic acid (DGLA) in peripheral fat storage tissue (Fig. 2). It binds to a secreted lipid chaperone protein (LBP-3) and induces a signaling pathway in neurons to promote longevity. Of importance in this process is the nuclear receptor NHR-49, which is a C. elegans homolog of PPARα. PPARα acts as transcription factor in mammalian neurons and mediates the induction of neuropeptide genes that have life-prolonging effects in the worm (e.g., the NLP-11). Nuclear receptors are known to be the major mediators of lipid signaling and have been more frequently associated with longevity recently.

Fig. 2 Mediation of non-cell autonomous regulation of lifespan by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), and the lipid chaperone protein LBP-3, which is transported from fat storage tissue to neurons. LBP-3 binds to DGLA and acts to extend lifespan via the nuclear receptor NHR-49 and the neuropeptide NLP-11 (modified Fig. 8i from Savini et al, 2022, Nat Cell Biol 24:906-916).

Taken together, the present work demonstrates that lysosome-derived signals not only regulate intercellular crosstalk but may also play an important role in tissue coordination in the organism. Whether lysosomes are truly relevant as signal mediators for the coordination of metabolism and aging in mammals remains to be seen. Overall, however, lipids represent important signals in tissue communication and could (e.g., in the form of dietary supplements) perhaps influence our lifespan. This has already been demonstrated for monounsaturated fatty acid (palmitoleic acid) uptake in the nematode.


Savini M, Folick A, Lee YT, ... , Ortlund EA, Wang MC (2022) Lysosome lipid signaling from the periphery to neurons regulates longevity. Nature Cell Biology 24:906

Image credit: iStock/Artur Plawgo


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