The essence of insect metamorphosis and aging: Electrical rewiring of cells driven by the principles of juvenile hormone-dependent Ca2+-homeostasis

• Farnesol-related sesquiterpenoids likely use Ca2+-ATPases as membrane receptors.
• The “status quo” effect of the farnesol-ester juvenile hormone (JH): keep [Ca2+]i low.
• The calcium-apoptosis link is causal to metamorphosis.
• Metamorphosis: the onset of accelerated insect progeria?
• Electrical rewiring of cells fits in the fading electricity theory of aging.

In holometabolous insects the fall to zero of the titer of Juvenile Hormone ends its still poorly understood “status quo” mode of action in larvae. Concurrently it initiates metamorphosis of which the programmed cell death of all internal tissues that actively secrete proteins, such as the fat body, midgut, salivary glands, prothoracic glands, etc. is the most drastic aspect. These tissues have a very well developed rough endoplasmic reticulum, a known storage site of intracellular Ca2+. A persistent high [Ca2+]i is toxic, lethal and causal to apoptosis. Metamorphosis becomes a logical phenomenon if analyzed from: (1) the causal link between calcium toxicity and apoptosis; (2) the largely overlooked fact that at least some isoforms of Ca2+-ATPases have a binding site for farnesol-like endogenous sesquiterpenoids (FRS). The Ca2+-ATPase blocker thapsigargin, like JH a sesquiterpenoid derivative, illustrates how absence of JH might work. The Ca2+-homeostasis system is concurrently extremely well conserved in evolution and highly variable, enabling tissue-, developmental-, and species specificity. As long as JH succeeds in keeping [Ca2+]i low by keeping the Ca2+-ATPases pumping, it acts as “the status quo” hormone. When it disappears, its various inhibitory effects are lifted. The electrical wiring system of cells, in particular in the regenerating tissues, is subject to change during metamorphosis. The possibility is discussed that in vertebrates an endogenous farnesol-like sesquiterpenoid, probably farnesol itself, acts as a functional, but hitherto completely overlooked Juvenile anti-aging “Inbrome”, a novel concept in signaling.

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