2019 Aging Conferences By Ben Best
Background Major recent advances in aging research have been so dramatic that many age-reversal therapies are becoming increasingly accessible. Some people are even self-experimenting with therapies before safety has been established in clinical trials. Three noteworthy examples will be described in detail. With aging, cells increasingly become malfunctional due to increasing DNA damage, especially due to shortening chromosomes (telomere shortening). These aged cells (senescent cells) are not only malfunctional, but have damaging effects on other cells. Removal of senescent cells can have rejuvenating effects, and one drug that does this is the prescription anticancer drug dastinib. Dastinib can reduce immune system cells, cause rash, and could harm the baby of a pregnant woman. Nonetheless, in most cases the drug is safe, especially when used only occasionally to eliminate senescent cells, rather than when used chronically to eliminate cancer cells. Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme required for the activity of sirtuins1 and the PARP (poly-(ADP-ribose) polymerase) enzymes used for DNA repair.2 When enzymes use NAD+, the NAD+ is converted to nicotinamide (NAM), which is either recycled to produce NAD+ or is methylated for excretion in the urine. There are seven human sirtuins (SIRT1-SIRT7) requiring NAD+ for stem cell function (maintaining healthy tissues),3 for DNA Repair,4 and for function of the energy-producing mitochondria in cells. Sirtuins for good mitochondrial function are especially important in organs requiring large amounts of energy, including the heart1 and the brain.5 Sirtuins activated by NAD+ inhibit the chronic inflammation associated with many aging-related diseases.6 Because NAD+ declines sharply with age,7 some people have taken intravenous NAD+ infusions, a process often associated with intense abdominal pain. Stress on the kidney or liver (possibly causing damage) might be the cause of this pain, but there has been no scientific investigation of this problem. Methylation is required to excrete the NAD+ waste product nicotinamide in the urine, a process which depletes the methylating agent s-adenosyl methionine, making it unavailable for other methylations.8 Although NAD+ at higher levels is beneficial to cells in general, it is also beneficial to senescent cells, worsening their damaging effects.9 www.alcor.org
Because NAD+ is a charged molecule, some scientists have thought that NAD+ cannot cross cell membranes. But one study found that specialized ion channels in neurons allow NAD+ to enter these brain cells,10 and another study found that these ion channels are not restricted to neurons.11 A study using radiolabeled NAD+ found that NAD+ was transported into six cell lines (fibroblast, neuroblastoma, HeLa, keratinocytes, macrophages, and endothelial cells).12 A pilot study of eleven human males (8 receiving NAD+ infusions, 3 controls) indicated tissue absorption of NAD+ during the first two hours, but after the first two hours the NAD+ (or nicotinamide) was mostly being excreted in the urine.13 Metformin has been shown to reduce cellular senescence in cells subject to senescent-causing stresses.14,15 Metformin also protects cells against inflammation due to Advanced Glycation Endproducts (AGEs).16 Metformin has been shown to promote brain cell genesis and improve memory in mice.17 Metformin also has health benefits by improving microbiota in the gut.18,19 In a very large clinical trial, type 2 diabetics treated with metformin lived 15% longer than non-diabetic subjects not taking metformin.20 One reason why type 2 diabetics have elevated blood glucose is that their livers produce glucose at twice the rate seen in normal subjects, but metformin reduces this glucose production by one-third.21 Metformin interferes with the distribution of iron in cells, a problem that can be partly corrected by taking iron supplements.22 The main sensor of cellular energy is AMPK (AMP-activated Protein Kinase).23 When cellular energy is depleted (low ATP, high AMP from ATP), AMPK reduces energy-utilizing metabolism and increases processes that produce the high energy ATP molecule.23 Recycling of damaged proteins for energy (autophagy) is one of the AMPK processes that is stimulated.23 AMPK increases NAD+ and sirtuin activity, which increases DNA repair and reduces chronic inflammation.24 Although metformin has been shown to activate AMPK in a variety of experiments, the amount of metformin required is much less than a person taking metformin would achieve in the usual doses.25,26 AMPK can be activated by lipoic acid,27 vinegar,28 resveratrol,29 curcumin,29 as well as by exercise and calorie restriction.29 A large clinical trial of nondiabetic persons comparing metformin with lifestyle (moderate exercise and diet) showed that lifestyle reduced the incidence of type 2 diabetes 58% over a 2.8-year period whereas metformin reduced the incidence by 31%.30
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