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When NNMT activity is elevated — as documented in obese adipose tissue, several cancer types, and aged skeletal muscle — intracellular NAD+ availability decreases, SAM availability decreases, and downstream sirtuin activity (particularly SIRT1 and SIRT3) is reduced

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When B12 levels become problematic: High-dose supplementation (particularly doses exceeding 1,000 micrograms daily) Frequent B12 injections without medical supervision Underlying conditions affecting B12 metabolism Concurrent use of multiple B12-containing supplements The NHS does not set an upper safe limit for vitamin B12 because harmful effects from excessive intake have not been definitively established