1 00:00:08,880 --> 00:00:09,320 Speaker 1: Hey folks. 2 00:00:09,360 --> 00:00:12,720 Speaker 2: Before the podcast, a quick announcement for me. I'm running 3 00:00:12,760 --> 00:00:16,160 Speaker 2: a special event called The Hardiness Effect. It's a full 4 00:00:16,239 --> 00:00:20,520 Speaker 2: day workshop plus six week app based program designed to 5 00:00:20,680 --> 00:00:24,680 Speaker 2: literally rewy your body and brand to thrive under pressure, 6 00:00:25,079 --> 00:00:28,440 Speaker 2: whilst helping you optimize your health and live longer. 7 00:00:28,880 --> 00:00:29,960 Speaker 1: Now, this isn't. 8 00:00:29,880 --> 00:00:34,040 Speaker 2: Fluffy self help bullship. 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Hey everybody, 36 00:02:13,520 --> 00:02:17,280 Speaker 2: welcome to another edition of Wisdom Wednesdays. Today I am 37 00:02:17,360 --> 00:02:21,520 Speaker 2: going to talk about some new research that offers a 38 00:02:21,600 --> 00:02:27,160 Speaker 2: little bit of tantalizing hope for Alzheimer's disease. And it 39 00:02:27,200 --> 00:02:30,559 Speaker 2: is all about a compound called lithium. 40 00:02:30,760 --> 00:02:33,560 Speaker 1: Now you may have heard of it before, you may not. 41 00:02:34,000 --> 00:02:38,200 Speaker 2: It has actually been used for decades as a psychiatric medication, 42 00:02:38,480 --> 00:02:42,720 Speaker 2: most famously for bipolar disorder. But what you probably don't 43 00:02:42,760 --> 00:02:46,760 Speaker 2: know is that lithium is also a naturally occurring trace 44 00:02:46,800 --> 00:02:50,440 Speaker 2: element that's found in our soil, our food, and even 45 00:02:50,840 --> 00:02:54,639 Speaker 2: more relevant for this, in our brains. And a recent 46 00:02:54,720 --> 00:02:58,639 Speaker 2: fascinating study out of Harvard Medical School has generated some 47 00:02:58,840 --> 00:03:03,960 Speaker 2: real buzz suggesting that tiny amounts of lithium, particularly in 48 00:03:04,000 --> 00:03:08,560 Speaker 2: a form called lithium or rotate, might have powerful effects 49 00:03:08,639 --> 00:03:13,720 Speaker 2: on brain aging and even help protect against Alzheimer's disease. Now, 50 00:03:13,960 --> 00:03:17,600 Speaker 2: before we start thinking we finally found the long awaited 51 00:03:17,720 --> 00:03:22,119 Speaker 2: silver bullet, let's really unpack the research and tell us 52 00:03:22,360 --> 00:03:25,560 Speaker 2: what is the state of play, what's exciting, what is 53 00:03:25,639 --> 00:03:30,760 Speaker 2: still speculative, and why we should be cautiously optimistic. So 54 00:03:30,880 --> 00:03:33,320 Speaker 2: let's first of all talk about the Alzheimer's challenge. You 55 00:03:33,360 --> 00:03:36,400 Speaker 2: would have heard me talk many times on this podcast 56 00:03:36,400 --> 00:03:41,120 Speaker 2: about Alzheimer's disease being one of medicine's greatest unsolved puzzles 57 00:03:41,160 --> 00:03:45,600 Speaker 2: because billions of dollars have been spent on drugs and 58 00:03:45,920 --> 00:03:49,640 Speaker 2: with no avaal to this point. Now, Alzheimer's is the 59 00:03:49,760 --> 00:03:54,320 Speaker 2: leading cause of dementia worldwide, and we really have only 60 00:03:54,520 --> 00:03:59,080 Speaker 2: made a very modest progress in its prevention and treatment, 61 00:03:59,800 --> 00:04:04,120 Speaker 2: and for decades it has been framed as an amyloid 62 00:04:04,320 --> 00:04:08,680 Speaker 2: versus tao battle, with these amyloid beta plaques and toy 63 00:04:08,960 --> 00:04:14,280 Speaker 2: tau tangles viewed as the central villains. But some researchers 64 00:04:14,360 --> 00:04:17,640 Speaker 2: have actually called that into question and said that even 65 00:04:17,680 --> 00:04:20,800 Speaker 2: though we see these things appear in the brain, they 66 00:04:21,000 --> 00:04:24,520 Speaker 2: might not be the cause. And this new study introduces 67 00:04:24,600 --> 00:04:27,840 Speaker 2: a third player. The trace element that we talked about 68 00:04:27,880 --> 00:04:32,280 Speaker 2: lithium measured in micrograms, and this might be very very important. 69 00:04:32,760 --> 00:04:37,080 Speaker 2: So in this harvardly had study, researchers examined post more 70 00:04:37,120 --> 00:04:41,479 Speaker 2: than brain tissue for people who had either normal cognition, 71 00:04:42,040 --> 00:04:46,040 Speaker 2: mild cognitive impairerment, which is often a precursor to Alzheimer's 72 00:04:46,080 --> 00:04:49,640 Speaker 2: or other forms of dementia, or full blown Alzheimer's disease. 73 00:04:50,120 --> 00:04:53,880 Speaker 2: And they measured twenty seven different metals and they find 74 00:04:54,000 --> 00:04:59,960 Speaker 2: that only lithium was consistently lower in people with cognitive decline, 75 00:05:00,520 --> 00:05:04,880 Speaker 2: and even more interestingly, lithium wasn't just missing, it was 76 00:05:04,920 --> 00:05:10,600 Speaker 2: actually misplaced. The team found that amyloid plaques actually trapped 77 00:05:10,640 --> 00:05:16,360 Speaker 2: lithium inside them, acting like molecular sponges, and that meant 78 00:05:16,440 --> 00:05:20,359 Speaker 2: that the brain regions most affected by Alzheimer's, particularly the 79 00:05:20,440 --> 00:05:25,840 Speaker 2: prefrontal cortex, were effectively lithium deficient, and the lower the 80 00:05:25,920 --> 00:05:30,280 Speaker 2: lithium levels in these healthy brain regions, the worst the 81 00:05:30,320 --> 00:05:34,560 Speaker 2: person's memory and cognitive test scores had been before death. 82 00:05:35,240 --> 00:05:40,719 Speaker 2: And this suggested that disrupted lithium distribution might not just 83 00:05:40,839 --> 00:05:43,720 Speaker 2: be a side effect, it could actually be part of 84 00:05:43,760 --> 00:05:48,520 Speaker 2: the disease process itself. So let's talk about testing the 85 00:05:48,520 --> 00:05:52,760 Speaker 2: theory what happens when the brain runs low on lithium. 86 00:05:53,080 --> 00:05:56,480 Speaker 2: So to explore that idea, the researchers turned to mouse models, 87 00:05:57,120 --> 00:06:02,200 Speaker 2: including what's called transgenic mice that develop Alzheimer's like pathology, 88 00:06:02,680 --> 00:06:06,040 Speaker 2: and they compare them to normal aging mice, and they 89 00:06:06,200 --> 00:06:11,320 Speaker 2: cut dietary lithium by about half, which in turn reduced 90 00:06:11,360 --> 00:06:13,960 Speaker 2: brain lithium levels by roughly fifty percent. 91 00:06:14,400 --> 00:06:16,360 Speaker 1: And what happened was remarkable. 92 00:06:16,839 --> 00:06:21,280 Speaker 2: Those lithium deficient mice began to show all the early 93 00:06:21,360 --> 00:06:26,320 Speaker 2: features of Alzheimer's disease, including more amyloid plaques and more 94 00:06:26,440 --> 00:06:33,160 Speaker 2: phosphorylated taul, increased brain inflammation, loss of synapses, axons, and 95 00:06:33,320 --> 00:06:37,000 Speaker 2: mile in sheath, which is the coating around the nerves 96 00:06:37,000 --> 00:06:41,359 Speaker 2: in the brain, and importantly clear deficits in learning and memory. 97 00:06:42,040 --> 00:06:46,880 Speaker 2: Even normal aging mice who don't usually develop amyloid pathology 98 00:06:47,320 --> 00:06:52,360 Speaker 2: showed faster cognitive decline when lithium was low. So just 99 00:06:52,720 --> 00:06:57,520 Speaker 2: lowering lithium alone was enough to trigger Alzheimer's like changes 100 00:06:57,560 --> 00:07:01,320 Speaker 2: in the brain. So let's talk about the molecular break 101 00:07:01,600 --> 00:07:05,599 Speaker 2: to understand how this happens. What the researchers did was 102 00:07:05,600 --> 00:07:08,160 Speaker 2: was looked at one of lithium's best known targets. It's 103 00:07:08,200 --> 00:07:12,559 Speaker 2: an enzyme and they all have silly, ridiculous earning names. 104 00:07:12,600 --> 00:07:19,480 Speaker 2: It's glycogen synthius kinikinis three beta or GSK three beta. 105 00:07:20,160 --> 00:07:23,920 Speaker 2: This enzyme is actually at the heart of Alzheimer's biology. 106 00:07:24,000 --> 00:07:26,240 Speaker 1: Now this gets a little bit complicated, but what it. 107 00:07:26,160 --> 00:07:32,360 Speaker 2: Does is it promotes tall phosphorylation, it drives amyloid production, 108 00:07:32,560 --> 00:07:37,480 Speaker 2: and it ramps up inflammation and under normal conditions, lithium 109 00:07:37,720 --> 00:07:41,680 Speaker 2: acts as a natural break on this enzyme, keeping X. 110 00:07:41,680 --> 00:07:42,800 Speaker 1: Activity in check. 111 00:07:43,320 --> 00:07:48,840 Speaker 2: But in the study, lithium deficiency unleashed this enzyme GSK 112 00:07:49,080 --> 00:07:53,200 Speaker 2: three beta, pushing it into a hyperactive state, and the 113 00:07:53,240 --> 00:07:56,600 Speaker 2: result was the perfect storm. When it comes to brain aging, 114 00:07:56,920 --> 00:08:02,600 Speaker 2: which included the development of tau tangles. In inflammation demilation 115 00:08:02,880 --> 00:08:05,840 Speaker 2: as in stripping off the mielin from the nerves and 116 00:08:05,960 --> 00:08:12,240 Speaker 2: synaptic loss, and when the researchers chemically blocked GSK three beta, 117 00:08:12,400 --> 00:08:17,040 Speaker 2: those changes largely reversed. So there's a real smoking gun here. 118 00:08:17,080 --> 00:08:21,600 Speaker 2: We understand the process and aim by damaging or stopping 119 00:08:21,640 --> 00:08:25,520 Speaker 2: the process, the damage actually reversed. And it's a really 120 00:08:25,560 --> 00:08:28,840 Speaker 2: strong hint that lithium's protective role in the brain may 121 00:08:28,880 --> 00:08:32,760 Speaker 2: stem from its ability to keep this enzyme under control. 122 00:08:33,840 --> 00:08:37,480 Speaker 2: So the next logical question is can we just give 123 00:08:37,559 --> 00:08:41,120 Speaker 2: lithium back If low lithium drives disease, can replacing it 124 00:08:41,240 --> 00:08:45,959 Speaker 2: fix the problem? In theory, yes, but the practical challenge 125 00:08:45,960 --> 00:08:50,440 Speaker 2: has always been formulation and safety. The lithium that has 126 00:08:50,600 --> 00:08:55,960 Speaker 2: typically been used clinically, lithium carbonate, is effective for mood disorders, 127 00:08:56,320 --> 00:09:00,920 Speaker 2: but comes with a very narrow therapeutic window. Doses high 128 00:09:01,040 --> 00:09:04,800 Speaker 2: enough to impact the brain can cause kidney and thyroid toxicity, 129 00:09:05,120 --> 00:09:09,680 Speaker 2: and in Alzheimer's most of that lithium ends up driven 130 00:09:09,720 --> 00:09:13,600 Speaker 2: into these amyloid plaques, where it's essentially useless. So the 131 00:09:13,679 --> 00:09:19,120 Speaker 2: Harvard team then screened sixteen different lithium salts to find 132 00:09:19,160 --> 00:09:23,760 Speaker 2: one that could deliver lithium into healthy Brian tissue without 133 00:09:23,960 --> 00:09:27,480 Speaker 2: binding to amyloid, and they found one that stood out, 134 00:09:27,840 --> 00:09:33,400 Speaker 2: and it's this lithium oratate. Lithium ritate is basically a 135 00:09:33,480 --> 00:09:36,920 Speaker 2: smarter delivery vehicle. It turned out to have a much 136 00:09:37,240 --> 00:09:40,440 Speaker 2: lower affinity for the amyloid plax, meaning it didn't drive 137 00:09:40,520 --> 00:09:44,520 Speaker 2: itself there and it stayed free in Brian tissue with 138 00:09:44,679 --> 00:09:48,600 Speaker 2: the neurons actually need it. And then the Alzheimer's prone 139 00:09:48,600 --> 00:09:53,160 Speaker 2: mice long term treatment with tiny doses of lithium oritate, 140 00:09:54,040 --> 00:09:57,680 Speaker 2: achieving blood levels similar to those seen naturally in humans, 141 00:09:58,160 --> 00:10:02,840 Speaker 2: actually produced dramatic effect. What they found was the amyloid 142 00:10:02,920 --> 00:10:07,600 Speaker 2: and tau accumulation were almost completely blocked, brain inflammation was 143 00:10:07,760 --> 00:10:13,880 Speaker 2: markeably reduced synaptic density and mielin integrity were preserved, and 144 00:10:14,000 --> 00:10:17,760 Speaker 2: on learning and memory tasks that traded mice performed as 145 00:10:17,760 --> 00:10:23,160 Speaker 2: well as cognitively normal controls. Even normal aging mice benefited. 146 00:10:23,559 --> 00:10:29,120 Speaker 2: Lithium ooritated reduced markers of brain inflammation, preserved synaptic connections, 147 00:10:29,520 --> 00:10:35,160 Speaker 2: and largely prevented age related cognitive decline, and crucially, it 148 00:10:35,280 --> 00:10:39,600 Speaker 2: did so at very low, non toxic doses. The doses 149 00:10:39,640 --> 00:10:43,679 Speaker 2: they used were several thousand times lower than those used 150 00:10:43,679 --> 00:10:49,080 Speaker 2: to treat bipolar disorder. So let's talk about human evidence. Now, 151 00:10:49,240 --> 00:10:53,000 Speaker 2: this obviously is still animal data and humans aren't big mice, 152 00:10:53,400 --> 00:10:56,520 Speaker 2: but there's alrarely a small body of human work hinting 153 00:10:56,520 --> 00:10:59,880 Speaker 2: that lithium could slow cognitive decline. Over the past two 154 00:11:00,520 --> 00:11:05,160 Speaker 2: several randomized trials have tested low dose lithium carbonate in 155 00:11:05,240 --> 00:11:09,360 Speaker 2: people with mild cognitive impairment or early Alzheimer's, and in 156 00:11:09,559 --> 00:11:13,960 Speaker 2: one two year study, lithium treatments stabilized memory and attention 157 00:11:14,440 --> 00:11:18,640 Speaker 2: while the placebo group declined, and their biomarker analysis that 158 00:11:18,679 --> 00:11:24,640 Speaker 2: they did showed reduced phosphorylated tawel and the higher levels 159 00:11:24,679 --> 00:11:28,000 Speaker 2: of alpha beta forty two in this cerebral spinal fluid, 160 00:11:28,320 --> 00:11:31,800 Speaker 2: which suggested slower amyloid accumulation. I know that's all a 161 00:11:31,800 --> 00:11:34,520 Speaker 2: bit geeky, but basically this is a good thing. And 162 00:11:34,559 --> 00:11:38,480 Speaker 2: then a smaller trial found that even microdoses three hundred 163 00:11:38,600 --> 00:11:43,360 Speaker 2: micrograms per day helps stabilize cognition in people already diagnosed 164 00:11:43,400 --> 00:11:47,720 Speaker 2: with Alzheimer's disease. When all the data are pulled, meta 165 00:11:47,760 --> 00:11:52,000 Speaker 2: analysis suggests that lithium therapy, usually in very low doses 166 00:11:52,440 --> 00:11:57,680 Speaker 2: produces the modest but measurable slowing of cognitive decline. And meanwhile, 167 00:11:57,920 --> 00:12:02,880 Speaker 2: observational data are are also interesting. People prescribe lithium for 168 00:12:03,080 --> 00:12:07,520 Speaker 2: mood disorders appear to have a roughly forty percent lower 169 00:12:07,640 --> 00:12:10,079 Speaker 2: risk of developing Alzheimer's disease. 170 00:12:10,559 --> 00:12:13,720 Speaker 1: And though you know, we've got to say that correlation. 171 00:12:13,320 --> 00:12:18,280 Speaker 2: Doesn't prove causation, but certainly evidence is starting to stack up. 172 00:12:18,679 --> 00:12:22,560 Speaker 2: Now what makes lithium oority it so exciting is that 173 00:12:22,600 --> 00:12:27,000 Speaker 2: it could overcome two major barriers that have limited lithium's 174 00:12:27,040 --> 00:12:31,560 Speaker 2: therapeutic potential, and that being the poor brain bioavailability ie 175 00:12:31,960 --> 00:12:35,800 Speaker 2: lithium's hard to be taken up by neurons and toxicity 176 00:12:35,840 --> 00:12:36,720 Speaker 2: at higher doses. 177 00:12:37,400 --> 00:12:38,959 Speaker 1: Because the lithium. 178 00:12:38,679 --> 00:12:41,840 Speaker 2: Orty it crosses the blood brain barrier more readily and 179 00:12:42,080 --> 00:12:46,560 Speaker 2: doesn't get trapped in amyloid, it could theoretically deliver the 180 00:12:46,640 --> 00:12:52,000 Speaker 2: same neuroprotective benefits at much lower, safer concentrations. And if 181 00:12:52,080 --> 00:12:56,280 Speaker 2: these findings translate to humans, we might finally have a 182 00:12:56,320 --> 00:13:01,120 Speaker 2: low dose, low toxicity way to restore natural levels of 183 00:13:01,160 --> 00:13:02,800 Speaker 2: lithium in the aging brain. 184 00:13:03,080 --> 00:13:06,079 Speaker 1: Now is still early days, but all of this. 185 00:13:06,160 --> 00:13:10,120 Speaker 2: Data provides a strong rationale for the first clinical trials 186 00:13:10,200 --> 00:13:14,920 Speaker 2: of lithium oritate in mild cognitive impoerment and early Alzheimer's disease, 187 00:13:15,760 --> 00:13:18,679 Speaker 2: and you can bet your bottom dollar they're already starting 188 00:13:18,720 --> 00:13:23,560 Speaker 2: to design these studies. Now, before you start googling lithium 189 00:13:23,679 --> 00:13:28,360 Speaker 2: oritate supplements, let's talk about safety and lithium in any 190 00:13:28,400 --> 00:13:33,319 Speaker 2: form is not something to just pop like vitamin C right. 191 00:13:33,800 --> 00:13:38,000 Speaker 2: Even tristosis can accumulate over time, and the margin between 192 00:13:38,040 --> 00:13:42,600 Speaker 2: therapeutic and toxic levels is pretty narrow. Lithium toxicity can 193 00:13:42,679 --> 00:13:46,400 Speaker 2: damage the kidneys, the thyroid, and in severe cases, the heart, 194 00:13:47,000 --> 00:13:50,760 Speaker 2: and we simply don't have enough long term safety data 195 00:13:50,800 --> 00:13:55,520 Speaker 2: on lithium ooritate in humans, particularly in older adults who 196 00:13:55,679 --> 00:14:00,600 Speaker 2: may already have reduced kidney function. So for ANWYE, this 197 00:14:00,640 --> 00:14:05,200 Speaker 2: is not a do it yourself experiment. Lithium should only 198 00:14:05,240 --> 00:14:09,839 Speaker 2: be used under medical supervision, with regular monitoring of seri 199 00:14:10,520 --> 00:14:14,640 Speaker 2: lithium levels, kidney function, and thyroid function. And it's also 200 00:14:14,679 --> 00:14:19,400 Speaker 2: worth noting that lithium is not recommended during pregnancy, as 201 00:14:19,440 --> 00:14:22,760 Speaker 2: it can cross the placenta and slightly increase the risk 202 00:14:22,800 --> 00:14:26,440 Speaker 2: of birth defects or pre term breaths. Now, despite all 203 00:14:26,440 --> 00:14:30,240 Speaker 2: of those caveats, and this study really does change how 204 00:14:30,240 --> 00:14:33,560 Speaker 2: we think about lithium. It reframes it as a nutrient 205 00:14:33,680 --> 00:14:37,720 Speaker 2: for brain resilience, something that the brain uses naturally to 206 00:14:37,840 --> 00:14:42,320 Speaker 2: keep key enzymes in signaling pathways and balance. And much 207 00:14:42,440 --> 00:14:47,480 Speaker 2: like ourn deficiency leads to anemia, a lithium deficiency might 208 00:14:47,600 --> 00:14:49,480 Speaker 2: accelerate neurodegeneration. 209 00:14:50,280 --> 00:14:54,280 Speaker 1: And restoring lithium to its physiological. 210 00:14:53,320 --> 00:14:57,600 Speaker 2: Range safely and in the right form could be one 211 00:14:57,680 --> 00:15:01,640 Speaker 2: piece of the Alzheimer's prevention puzzle, although we're not there yet, 212 00:15:01,800 --> 00:15:05,960 Speaker 2: so I'm not recommending that you go out and take 213 00:15:06,080 --> 00:15:07,640 Speaker 2: lithium or go out and buy it. 214 00:15:08,960 --> 00:15:11,000 Speaker 1: Do I take it? Yes, I do. 215 00:15:11,160 --> 00:15:14,760 Speaker 2: Because of this, I take lithium or TAD five milligrams 216 00:15:14,840 --> 00:15:17,640 Speaker 2: a couple of times a week. But I am not 217 00:15:17,720 --> 00:15:21,240 Speaker 2: suggesting that you do this, and I am certainly suggesting 218 00:15:21,280 --> 00:15:24,440 Speaker 2: that you talk to your doctor if you're even thinking 219 00:15:24,520 --> 00:15:28,480 Speaker 2: about taking any form of lithium at all. But this 220 00:15:28,840 --> 00:15:33,960 Speaker 2: certainly is a very, very exciting development, and I'm sure 221 00:15:34,000 --> 00:15:38,480 Speaker 2: that there are clinical trials right now being designed and 222 00:15:38,560 --> 00:15:43,080 Speaker 2: registered both to determine the safe and affected dose of it, 223 00:15:43,200 --> 00:15:45,480 Speaker 2: just like any drug has to go through that process 224 00:15:46,080 --> 00:15:50,240 Speaker 2: and then as interventions for people with Alzheimer's disease and 225 00:15:50,320 --> 00:15:55,200 Speaker 2: mild cognitive impowerment. But it is certainly a space that 226 00:15:55,400 --> 00:15:59,120 Speaker 2: is worth watching and that I think we will get 227 00:15:59,160 --> 00:16:01,400 Speaker 2: to those answers pretty dumb quickly. 228 00:16:02,080 --> 00:16:04,600 Speaker 1: So that's it for this weeaks folks. Catch you next time.