by William Clearfield, D.O. for Longevinex
At the age of 73, Teddy began forgetting things. At first, it was cute. He put his car keys in the freezer, forgot his grandchildren’s names, and missed an appointment with me that he didn’t remember he had.
I’ll never forget the day I got the call that Teddy had driven his car through the back wall of his garage, wiping out the sink, stove, and refrigerator in his kitchen.
This was not normal.
I knew what was wrong, but without testing, I’ve learned over the years to keep it to myself until I am sure. I never wanted to alarm Teddy or Stephanie, his wife, until I was certain. It was clear, however, after the blood tests, psychological profiles, and brain scans, where Teddy stood when eliminating all of the physical possibilities.
I love being a doctor. This, however, was the worst part of the job. Delivering bad news in any line of work is difficult. As a doctor, providing this type of news is the equivalent of a death sentence. This is not what I signed up for.
“Alzheimer’s Disease,” I said.
Teddy stared off into space. Steph looked stunned at first, then nodded. I’m certain this was what she suspected all along.
“Are you sure?” she asked.
I assured her I was as sure as possible in this situation.
“Memory loss, getting lost on the way to the grocery store. He forgets where he is. Does he repeat what he just said and not remember saying it the first time?”
Steph nodded yes.
“Stopping in the middle of conversations. Depth perception problems not related to eye diseases?”
“Yes, and yes,” she said. “And he’s been mean to the grandbabies. He accused the five-year-old of stealing money out of his wallet.”
“Not being able to handle any new information,” I said.
“Unfortunately,” Steph replied, tears in her eyes. “It’s been going on for at least a year now. We tried laughing it off at first. But we can’t put it off any longer. Thank God he only destroyed the Frigidaire, the stove, and the car. Next time it could be himself or someone else.”
“No more driving,” I said. “I have to report this to the DMV.”
“I know,” she replied quietly, “I know.”
“There are two types of FDA medications, one aimed at changing the disease’s progression and the other that mitigates some symptoms—the cognitive loss. We will send Teddy to a neurologist for those.
I discussed with Ted and Steph a relatively common, inexpensive metabolic “superstar,” resveratrol.
“We need to be clear,” I said, “Resveratrol is not a ‘cure’ by any means. But with regular use, we’ve found it to alleviate many of the same symptoms and delay the onset of further deterioration of Teddy’s brain.”
“What is it?” Teddy asked.
“Resveratrol is a natural polyphenol compound found in grapes, berries, peanuts, red wine, and giant knotweed. (Resveratrol was the subject of two previous posts concerning polycystic ovary syndrome and cardiovascular disease.) (1-2)
“How does this happen?” Steph asked.
“Alzheimer’s disease arises out of chronic inflammation, genetic predispositions, and aging resulting in the self-assembly of proteins named Amyloid A. Amyloid A proteins suffer from neurodegenerative diseases typified by Alzheimer’s and Parkinson’s Disease. (3)
The pathological processes we discussed with cardiovascular disease, reactive oxidative stress, a disturbance in the balance between productive oxygen consumption and neutralizing antioxidants, and dysregulation of cholesterol metabolism occur in the carotid and cerebral blood vessels leading to the aforementioned neurodegenerative deterioration. (4-5)
Resveratrol slows and, in some cases, reverses this destructive process. (6) A key component in unlocking the mystery of neurodegenerative diseases is something we’ve discussed at length in other contexts: cholesterol.
Cholesterol and the Brain
60% of our brain tissue is cholesterol. Cholesterol plays a vital role in regulating membrane permeability and participates in signaling pathways directing the maintenance of brain health. Like neurosteroid hormones, specifically testosterone, estradiol, DHEA, progesterone, and pregnenolone, cholesterol is generated and regulated endogenously within the brain due to the blood-brain barrier. (7-8) Normal cholesterol production and metabolism are critical to adequate cerebral function.
Aging, among other joys, increases aberrant cholesterol staging and metabolism. We can conclude that cholesterol controls the amyloid pathway resulting in the accumulation of the aforementioned toxic Amyloid A proteins. (9) Maturity has a significant effect on free cholesterol levels. (10) Apolipoprotein E (APOE), a gene that regulates cholesterol homeostasis, influences the trajectory of total cholesterol, HDL cholesterol, and the total: HDL cholesterol ratio from midlife through late life. (11) APOE e2+ patients exhibit higher HDL and lower total cholesterol levels and statistically significant longer lifespans, from midlife to late life, compared to APOE e3 and APOE e4+ subjects.
These differences extended to gender and the use of cholesterol-lowering medications. (12) Two key enzymes, (1) the cytosolic hydroxymethylglutaryl-CoA synthase (HMG-CoA-C1) and (2) 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R) regulate cholesterol synthesis. (13)
Age and resveratrol treatment affect the levels of these two enzymes negatively and positively, respectively. (14-15) Resveratrol’s Role in Delaying Neurodegeneration Cholesterol metabolism and resveratrol’s effect on the brain differ depending on one’s age. (16) Resveratrol prevents amyloid-induced neuronal changes and high-fat diet-induced cognitive decline. (17) It reduces LDL-(bad cholesterol) oxidized levels and improves lipid-lowering efficacy in hepatic cells while triggering neuroprotective signals. (18)
In an animal (SAMP8 mouse) model of aging and Alzheimer’s disease, Sanchez-Melgar, et al. found free cholesterol levels in 7-month-old mice significantly higher than in 5-month-old mice. (The lifespan of a SAMP8 mouse is approximately ten months of age. A 5-month-old mouse is equivalent to ages 38-47 in human years, and a 7-month-old mouse reflects 56-69 human years.) (21) Early treatment with resveratrol resulted in a statistically significant decrease in LDL (bad) cholesterol in the five-month-old, but no change in the 7-month-old mice. Similarly, the ApoE levels showed a marked reduction after resveratrol input. (20) Total cholesterol levels increase both with age and resveratrol therapy. However, resveratrol increases HDL, good cholesterol, to the level rendering any increase in total cholesterol moot. Aging without resveratrol perpetuates the downhill spiral of cholesterol-related damage. (21) As for HDL (“good”) cholesterol, resveratrol increased HDL levels in the middle age (5-month-old) mice but had little effect on the older 7-month-olds. (22)
Essential for the brain to function correctly, cholesterol dysregulation as the result of genetic, environmental, or aging insults results in synaptic failure and memory impairment. Cholesterol-lowering drugs, particularly statins, may be effective against AD incidence.
Age-dependent increases in free cholesterol in the plasma membrane isolated from the brains of SAMP8 mice suggest a dysregulation in the form of cell membrane rigidity in cholesterol metabolism within the CNS. This “stiffening” of neuronal cell membranes diminishes neurotransmission of essential components, including nutrients, proteins, and minerals. Decreased nutrients lead to neurotransmitter deficits with subsequent rearranging of the dysregulated proteins into amyloid B bodies, cognitive and memory decline, and in the most extreme cases, Alzheimer’s Disease or other neurodegenerative maladies.
Early midlife intervention with adequate doses of resveratrol clearly shows a reduction in many pathways leading to neurodegenerative disease. Not intervening until later in life, the 6th or 7th decade, according to the mouse model, is less effective but does yield some benefit.
In younger mice, resveratrol reduces cholesterol uptake via LDL-R, increasing the levels of HMG-CoA reductase and HMG-CoA-C1 synthase, lowering cholesterol levels in the brain. In older mice, resveratrol reduces cholesterol uptake via LDL-R, increasing cholesterol release. The blood-brain barrier prevents the direct cholesterol exchange between blood and the brain. Peripheral cholesterol rises with age. Resveratrol supplementation increases HDL levels in five-month-old but not seven-month-old mice. The effect of resveratrol supplementation on HDL levels depends on the health status of each individual.
Age is a prominent factor for cholesterol metabolism impairment. Resveratrol supplementation exhibits different neuroprotective effects depending on the age of initiation of therapy. “
Why didn’t you tell me sooner,” Teddy asked.
“As I recall,” I replied, “you know everything about everything. Would you have listened if I told you to take resveratrol when you were 50?” Teddy began to protest, but Steph cut him off. “Of course not,” she said. “He didn’t listen then. Maybe, he will listen now.”
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- Clearﬁeld, W., Reducing Your Risk Of Cardiovascular Diseases With Natural Compounds, April 2023 https://longevinex.com/reducing-risk-of-cardiovascular-diseases/
- Clearﬁeld, W., Resveratrol Use in Polycystic Ovarian Syndrome, https://longevinex.com/resveratrol-use-in-polycystic-ovarian-syndrome/
- Chen, G. F., Xu, T. H., Yan, Y., Zhou, Y. R., Jiang, Y., Melcher, K., & Xu, H. E. (2017). Amyloid beta: structure, biology and structure-based therapeutic development. Acta pharmacologica Sinica, 38(9), 1205–1235. https://doi.org/10.1038/aps.2017.28
- Betteridge DJ. What is oxidative stress? Metabolism. 2000;49(2 Suppl 1):3-8. doi:10.1016/s0026-0495(00)80077-3
- Liu T, Qi H, Ma L, et al. Resveratrol Attenuates Oxidative Stress and Extends Life Span in the Annual Fish Nothobranchius guentheri. Rejuvenation Res. 2015;18(3):225-233. doi:10.1089/rej.2014.1618
- Juarez D, Arteaga I, Cortes H, Vazquez-Roque R, Lopez-Lopez G, Flores G, Treviño S, Guevara J, Diaz A. Chronic resveratrol administration reduces oxidative stress and brain cell loss and improves memory of recognition in old rats. Synapse. 2023 May 2:e22271. doi: 10.1002/syn.22271. Epub ahead of print. PMID: 37130656.
- Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113-137. doi:10.1016/B978-0-444-53630-3.00008-7
- Zhang J, Liu Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell. 2015;6(4):254-264. doi:10.1007/s13238-014-0131-3
- Rudajev V, Novotny J. Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease. Front Mol Neurosci. 2022;15:937056. Published 2022 Aug 25. doi:10.3389/fnmol.2022.937056
- Downer B, Estus S, Katsumata Y, Fardo DW. Longitudinal trajectories of cholesterol from midlife through late life according to apolipoprotein Eallele status. Int J Environ Res Public Health. 2014;11(10):10663-10693. Published 2014 Oct 16. doi:10.3390/ijerph111010663
- Genomes Project C., Abecasis G.R., Auton A., Brooks L.D., dePristo M.A., Durbin R.M., Handsaker R.E., Kang H.M., Marth G.T., McVean G.A. An integrated map of genetic variation from 1092 human genomes. Nature. 2012;491:56–65.
- Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002 Aug 6;137(3):149-55. doi: 10.7326/0003-4819-137-3-200208060-00006. PMID: 12160362.
- DeBose-Boyd, R. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18, 609–621 (2008). https://doi.org/10.1038/cr.2008.61
- Trapani L, Pallottini V. Age-Related Hypercholesterolemia and HMG-CoA Reductase Dysregulation: Sex Does Matter (A Gender Perspective). Curr Gerontol Geriatr Res. 2010;2010:420139. doi:10.1155/2010/420139
- Villanueva JA, Sokalska A, Cress AB, et al. Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells. J Clin Endocrinol Metab. 2013;98(3):E455-E462. doi:10.1210/jc.2012-3387
- Sánchez-Melgar A, Izquierdo-Ramírez PJ, Griñán-Ferré C, Pallàs M, Martín M, Albasanz JL. Neuroprotective Effects of Resveratrol by Modifying Cholesterol Metabolism and Aβ Processing in SAMP8 Mice. Int J Mol Sci. 2022 Jul 8;23(14):7580. doi: 10.3390/ijms23147580. PMID: 35886936; PMCID: PMC9324102.
- Yang, A. J. T., Bagit, A., & MacPherson, R. E. K. (2021). Resveratrol, Metabolic Dysregulation, and Alzheimer’s Disease: Considerations for Neurogenerative Disease. International journal of molecular sciences, 22(9), 4628. https://doi.org/10.3390/ijms22094628
- Akbari, M., Tamtaji, O. R., Lankarani, K. B., Tabrizi, R., Dadgostar, E., Haghighat, N., Kolahdooz, F., Ghaderi, A., Mansournia, M. A., & Asemi, Z. (2020). The effects of resveratrol on lipid proﬁles and liver enzymes in patients with metabolic syndrome and related disorders: a systematic
“Doc,” Teddy said, “I looked up this ‘revers-it-all’ stuff you gave me.” “Resveratrol,” I replied. “Right, reverse-it-all, Teddy replied. “There’s like at least fifty ways it helps.” “Sounds like a song,” I replied. “Paul Simon,” […]
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