Potential Anti-Aging and Neuroprotection Strategy for Parkinson’s

“The years teach much which the days never know.” Ralph Waldo Emerson

“Old age is not a disease – it is strength and survivorship, triumph over all kinds of vicissitudes and disappointments, trials and illnesses.” Maggie Kuhn

Introduction: This blog post presents a strategy to possibly reduce aging and it may also be neuroprotective in the Parkinson’s brain. The idea was presented by Professor Oliver T. Phillipson and tested/validated by others; I find it is both scientifically sound and very interesting. This is my attempt to explain how a strategy to reverse aging could be especially beneficial for people with Parkinson’s and likely valuable for older adults, in general. Let’s start by trying to define the meaning of the word “aging.”

“We don’t stop playing because we grow old; we grow old because we stop playing.” George Bernard Shaw

Defining Aging:
A Scientific Definition of Aging from the textbook book Developmental Biology says that “Aging can be defined as the time-related deterioration of the physiological functions necessary for survival and fertility. The characteristics of aging—as distinguished from diseases of aging (such as cancer and heart disease)—affect all the individuals of a species.”

As defined by Wikipedia “Ageing or aging (see spelling differences) is the process of becoming older. … In the broader sense, ageing can refer to single cells within an organism which have ceased dividing (cellular senescence) or to the population of a species (population ageing).”

The National Institute of Aging at the NIH says that “Aging is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes. Some age-related changes are benign, such as graying hair. Others result in declines in function of the senses and activities of daily life and increased susceptibility to and frequency of disease, frailty, or disability. In fact, advancing age is the major risk factor for a number of chronic diseases in humans.”

From the textbook “Evolutionary Biology of Aging,” M.R. Rose defines aging as “a persistent decline in the age-specific fitness components of an organism due to internal physiological degeneration.”

“We’ll never be as young as we are tonight.” Chuck Palahniuk

The Aging Process: Simply put, aging is the process of growing old, regardless of chronological age. What causes us to age? It could be answered a hundred different ways by a hundred scientists/clinicians that focus their research on aging. I spent several years at the end of my research career focused on aging in cardiovascular health (NIH funding from the National Institute of Aging and Institute of Heart, Lung, and Blood, for a project entitled “p16INK4a, Senescence and Aging in Venous Thromboembolism”).

Aging is the process that progressively increases an individual’s susceptibility to various factors that cause death, and this process includes a loss of all physiological functions including reproductive capacity.

Multicellular organisms have a natural defense against cancer when cells/tissues are presented with an alternative fate that includes apoptosis and senescence.  By design, apoptosis leads to cell death and tissue loss, while senescence allows the cell to remain metabolically active despite the inability of further cellular division. 

We describe senescence as a state of essentially permanent cell cycle arrest that a cell adopts in response to abnormal proliferative signals, intracellular stress, or DNA damage.  The word senescence is derived from the Latin word senex, meaning “old man” or “old age.” 

“Every time I think that I’m getting old, and gradually going to the grave, something else happens.” Elvis Presley

The Biological Mechanism of Aging: There are many theories for aging; thus, there is not a consensus on what causes aging. Here are some possibilities that seem to make sense with regards to idiopathic Parkinson’s and an aging brain. Included below are brief descriptions for oxidative damage, mitochondrial genome damage, genetic instability and generic wear-and-tear, telomere shortening, and genes of aging.

•Oxidative damage- Our own metabolism causes damage to cells/tissues by generating reactive oxygen species (ROS). These highly reactive substances (e.g., superoxide ion, hydroxyl radical, and hydrogen peroxide) attack, and oxidize host cell membranes, proteins, and nucleic acids.

Mitochondrial gene modification- Mutations in the genome of mitochondria can promote changes in energy production, increased ROS production, and even the induction of apoptosis. 

Genetic instability and overall wear-and-tear syndrome- As we age, we generate small regions of trauma in cells and tissues, which ultimately result in the generation/production of defective/faulty proteins.  As these mutations start to accumulate, repairing them and regenerating the tissue becomes more difficult, ultimately reducing the cell/tissue/organ life expectancy. This wear-and-tear hypothesis would lead to a phenotype that most-likely resembles senescence.

Telomeres Shortening- Telomeres are DNA sequences that are repeated at the ends of chromosomes. After each cell division, they are shortened because they are not replicated by DNA polymerase.  However, if present, telomerase adds the telomere onto the chromosome at each cell division. Most mammalian tissues do not have telomerase, which implies that telomere shortening could be considered a “biological clock” to ultimately prevent cells from dividing.

•Genes of Aging- Various species have genes related to aging. In humans as an example, we have Hutchinson-Gilford progeria syndrome, which results in rapid aging and death to affected children usually by the age of 12 years old.

“There is still no cure for the common birthday.” John Glenn

Anti-Aging and Parkinson’s: The biggest risk factor for Parkinson’s is advanced age. While there is no doubt a prominent and important group of young patients with early-onset Parkinson’s, the vast majority of people are older than 65 years of age (see figure below for some of the causes of the disorder).

“Aging is not “lost youth” but a new stage of opportunity and strength.” Betty Friedan

Nutritional Substances that Might Work Together to Manage Aging: This is not about a ‘Fountain of Youth’, these compounds have been studied in research laboratories using cells grown in plastic plates, in animal models of diseases, and being sold to many and hailed as anti-aging compounds. That is for you to decide. What got me interested in these molecules was a wonderful review by Professor Phillipson (Phillipson, O.T. Management of the Aging Risk Factor for Parkinson’s Disease. Neurobiology of aging. 2014, 35,4, 847-857). This was preceded by a case study (Phillipson, O.T. Inhibition of Aging in Parkinson’s Disease: A Case Study. The Journal of Alternative and Complementary Medicine. 2013, 19,10, 851-851).

The compounds being studied were as follows: a (alpha)-Lipoic acid (ALA), acetyl-L-carnitine (ALC), melatonin, and coenzyme Q10 (CoQ). Likely, the only substance you have recognized is melatonin. However, the properties being described below are less related to its property to aid sleep and more related to its potent antioxidant action in mitochondria. Since I am an old-time biochemist, I start with showing their molecular structures (See Figure below).

“Life can only be understood backwards; but it must be lived forwards.” Soren Kierkegaard

Combining ALA, ALC, CoQ, and Melatonin Could Possibly be Anti-aging and Neuroprotective: To summarize a bunch of observations together, I have prepared this Figure. On the left side are some of the events that happen in mitochondria within our cells that initiate an aging process. On the right side of the Figure are some of the known properties found for these four substances in ‘reversing’ or ‘preventing’ these aging event. And there is a reported synergistic effect between ALA and ALC, and then further additional events may occur with all 4 compounds.

Side Note: You may be asking yourself what are mitochondria? Wikipedia in a simplest manner says this: “Mitochondria (sing. mitochondrion) are organelles, or parts of a eukaryote cell. They oxidise glucose to provide energy for the cell. The process makes ATP, and is called cellular respiration. This means mitochondria are known as ‘the powerhouse of the cell’.” [https://simple.wikipedia.org/wiki/Mitochondria ]. From this definition you can gather they are part of the machinery in our cells responsible for generating energy. They process substances and they provide key power to keep our cells, tissues, organs , body alive and functioning. Think of an automobile with a dead engine, now consider the mitochondria like that engine, when the engine is working the car is usually moving. The middle part of the figure below has a schematic drawing of a mitochondrion.

“Age considers; youth ventures.” Rabindranath Tagore

Individual Properties of ALA, ALC, CoQ, and Melatonin That Suggest a Potential Role to be Anti-aging and Neuroprotective in Parkinson’s (References are given at the bottom of the post.)

a-Lipoic Acid:

  • a-Lipoic Acid (ALA) is essential for cell growth, mitochondrial activity, and coordination of fuel metabolism [1].
  • ALA is synthesized in both plants and animals; however, its production in humans is low.  Broccoli, spinach, tomatoes, peas, brown rice, potatoes, and red meat are especially rich in ALA [2].
  • Highlighting two of the many earlier studies with ALA, Stoll et al. showed that memory improved when old rodents were given ALA, but this did not happen in younger animals [3].
  • Hagen et al. found that cells from the aged animals were more susceptible to oxidative insult than young cells.  However, this age-related increase in oxidative vulnerability is reversed by exogenously added ALA after its reduction to an antioxidant in the mitochondria [4].
  • Phillipson nicely updated the known properties of ALA in neuronal tissue and how beneficial supplementation with it could help to manage the biology of advanced aging either in the absence or in the presence of PD [5].
  • Please note that ALA may lower thyroid hormone; thus, PwP with hypothyroidism should avoid taking ALA.

Acetyl-L-Carnitine:

  • L-Carnitine can be produced from the amino acids Methionine and Lysine and is considered both a nutrient and a supplement [6].
  • L-Carnitine has an essential function in facilitating the production of energy due to the role it plays in generating energy through the transportation of fatty acids in mitochondria [6].
  • Furthermore, the acetylated form of L-Carnitine (ALC) seems especially beneficial for the brain [7].
  • As mentioned above for ALA, ALC partially restored mitochondrial function in aged but not young rat cells [8].
  • Furthermore, ALC partially reversed both memory and learning defects found in aged rat brains, but not in young rat brains [9].
  • Several studies suggest that combining ALA and ALC could reverse the aged-link decline in the brain, and potentially be neuroprotective in the progression of PD [5, 10-12].

Melatonin:

  • Melatonin is derived from the amino acid tryptophan [13].
  • All multicellular animals apparently possess melatonin.  There are many function for melatonin acquired throughout evolution [14].
  • A key function of melatonin is its function in enabling sleep through the circadian cycle [15].
  • One of the long-term issues with the brain is the potential to generate reactive oxygen species (ROS), partly due to its high oxygen use.  Coupled with large amounts of polyunsaturated fatty acids, iron, and relatively low levels of natural antioxidants, oxidative damage in the brain increases with age [16]. 
  • A potent action of melatonin is to be a scavenger of both activated oxygen and nitrogen species, partly by increasing glutathione peroxidase, copper-zinc superoxide, and manganese superoxide dismutase.
  • And many aspects of the brain diminish in function (e.g., cognition and motor functions) with respect to aging [17, 18].
  • And with oral ingestion of melatonin, it is free to access the brain and promote wellness as an anti-oxidant and to help mitochondria by increasing ETC activity and further production of ATP.

Coenzyme Q:

  • CoQ has a notable role in the ETC found in the inner membrane of the mitochondria.  The process of electron transport cycles to give the release of electrons, which ultimately maintains the membrane potential and viability of the mitochondria.
  • Outside of the membrane, in its reduced form of ubiquinol, CoQ acts as an antioxidant [19].
  • In separate clinical trials, CoQ has given different outcomes in PD when used alone [20]. 
  • However, as suggested by Phillipson [5], there could be real potential to alter progression when CoQ is paired with other substances.

“Age is an issue of mind over matter. If you don’t mind, it doesn’t matter.” Mark Twain

Putting the Pieces of the Puzzle Together:

  • ALA and ALC- Hagen et al. (1998 and 2002) found that combining ALC and ALA together gave partial reversal of age to hepatocytes [8, 21]. And this was further verified using brain cell-derived mitochondria [22].  Aliev et al. found that mitochondria were restored in the brains of aged rats [11]. Zhang et al. found that ALA and ALC reduced the accumulation of alpha-synuclein and also activated the Nrf2 antioxidant system [10].
  • CoQ and ALA- Phillipson suggested that combining ALA and CoQ could provide neuroprotection in PD due to the expression provided by Nrf2 for protection of dopaminergic neurons [5].
  • Melatonin with ALA, ALC, and CoQ– Aging has been found to reduce melatonin secretion [13]. Addition of small amounts of melatonin may provide sleep help and also prevent some oxidative damage from the aging process in mitochondria. Sharma et al. showed in an animal model of Parkinson’s that melatonin was neuroprotective [23].
SubstanceAmount Taken and FrequencyBrand and Source
α-Lipoic acid600 mg capsule dailySuperior Labs, Amazon.com (https://amzn.to/2RLVQws)
Acetyl-l-carnitine500 mg capsule dailyDouble Wood Supplements, Amazon.com (https://amzn.to/2t0Gyvz)
Melatonin3 mg dissolving tablet daily at nightNatrol, Amazon.com (https://amzn.to/3wNhELn)
Coenzyme Q10100 mg capsule dailyNOW Supplements, Amazon.com (https://amzn.to/3vyn6RY)
*Coenzyme Q10 + Alpha Lipoic Acid + Acetyl L-Carnitine HCl  2 capsules daily, contains 200 mg CoQ, 300 mg ALA and 500 mg ALCNature’s Lab, Amazon.com (https://amzn.to/3wMvAoR) *NOTE: I just saw this on the Amazon.com website that all 3 compounds are available together.  I have not used this product.

“Anyone who stops learning is old, whether at twenty or eighty. Anyone who keeps learning stays young. The greatest thing in life is to keep your mind young.” Henry Ford

Conclusions: If you have read this far in this meandering blog post, you are either reading it to cure insomnia, a family member always loyal to the very end, or you are really interested in the background and use of these Complementary and Alternative Medicine (CAM) substances.

I am not here to tell you to take these substances because I know how likely it is you are already taking many tablets/capsules per day. Personally, I have been taking ALA (600 mg/day) and ALC (500 mg/day) for about 2 years. Off and on, I have been taking melatonin (3 mg at night), and a few years ago, I used CoQ but stopped following publication of the clinical trials.

Recently, I had a review published on treating motor and non-motor symptoms of Parkinson’s [24]. I suggested there were five treatment options for Parkinson’s: rehabilitate, therapy, restorative, maintenance, and surgery. The option of Maintenance uses CAM substances that potentially support and protect the brain microenvironment.  The compounds described in this post are most likely used to maintain the dopamine-producing neurons I have left in my brain.

My goal is to do what seems logical from what I have read and reasoned from the medical literature.  As I have said here many times, this is not medical advice; however, I have always presented issues and substances that I have used personally.  The best medicine for Parkinson’s is still exercise but I do believe helping maintain the health of my brain microenvironment is useful with a reasonable CAM strategy.

“I live in that solitude which is painful in youth, but delicious in the years of maturity.” Albert Einstein

Cover photo image by Steve Bidmead from Pixabay

References Cited:

1.         Solmonson, A.; DeBerardinis, R.J. Lipoic Acid Metabolism and Mitochondrial Redox Regulation. Journal of Biological Chemistry. 2018, 293,20, 7522-7530.

2.         Lodge, J.K.; Packer, L. “Natural Sources of Lipoic Acid in Plant and Animal Tissues.” In Antioxidant Food Supplements in Human Health, 121-134: Elsevier, 1999.

3.         Stoll, S.; Rostock, A.; Bartsch, R.; Korn, E.; Meichelböck, A.; Müller, W. The Potent Free Radical Scavenger Α‐Lipoic Acid Improves Cognition in Rodents. Annals of the New York Academy of Sciences. 1994, 717,1, 122-128.

4.         Hagen, T.M.; Vinarsky, V.; Wehr, C.M.; Ames, B.N. (R)-Α-Lipoic Acid Reverses the Age-Associated Increase in Susceptibility of Hepatocytes to Tert-Butylhydroperoxide Both in Vitro and in Vivo. Antioxidants and Redox Signaling. 2000, 2,3, 473-483.

5.         Phillipson, O.T. Management of the Aging Risk Factor for Parkinson’s Disease. Neurobiology of aging. 2014, 35,4, 847-857.

6.         Bremer, J. Carnitine–Metabolism and Functions. Physiological reviews. 1983, 63,4, 1420-1480.

7.         Bremer, J. Carnitine in Intermediary Metabolism. J. biol. Chem. 1962, 237,3628-3632, 677.

8.         Hagen, T.M.; Ingersoll, R.T.; Wehr, C.M.; Lykkesfeldt, J.; Vinarsky, V.; Bartholomew, J.C.; Song, M.-H.; Ames, B.N. Acetyl-L-Carnitine Fed to Old Rats Partially Restores Mitochondrial Function and Ambulatory Activity. Proceedings of the National Academy of Sciences. 1998, 95,16, 9562-9566.

9.         Kobayashi, S.; Iwamoto, M.; Kon, K.; Waki, H.; Ando, S.; Tanaka, Y. Acetyl‐L‐Carnitine Improves Aged Brain Function. Geriatrics & gerontology international. 2010, 10 S99-S106.

10.       Zhang, H.; Jia, H.; Liu, J.; Ao, N.; Yan, B.; Shen, W.; Wang, X.; Li, X.; Luo, C.; Liu, J. Combined R‐Α–Lipoic Acid and Acetyl‐L‐Carnitine Exerts Efficient Preventative Effects in a Cellular Model of Parkinson’s Disease. Journal of cellular and molecular medicine. 2010, 14,1‐2, 215-225.

11.       Aliev, G.; Liu, J.; Shenk, J.C.; Fischbach, K.; Pacheco, G.J.; Chen, S.G.; Obrenovich, M.E.; Ward, W.F.; Richardson, A.G.; Smith, M.A. Neuronal Mitochondrial Amelioration by Feeding Acetyl‐L‐Carnitine and Lipoic Acid to Aged Rats. Journal of cellular and molecular medicine. 2009, 13,2, 320-333.

12.       Phillipson, O.T. Inhibition of Aging in Parkinson’s Disease: A Case Study. The Journal of Alternative and Complementary Medicine. 2013, 19,10, 851-851.

13.       Escames, G.; López, A.; García, J.A.; García, L.; Acuña-Castroviejo, D.; García, J.J.; López, L.C. The Role of Mitochondria in Brain Aging and the Effects of Melatonin. Current neuropharmacology. 2010, 8,3, 182-193.

14.       Hardeland, R.; Poeggeler, B. Non‐Vertebrate Melatonin. Journal of pineal research. 2003, 34,4, 233-241.

15.       Karasek, M. Melatonin, Human Aging, and Age-Related Diseases. Experimental gerontology. 2004, 39,11-12, 1723-1729.

16.       Escames, G.; Macias, M.; Leon, J.; Garcia, J.; Khaldy, H.; Martin, M.; Vives, F.; Acuña‐Castroviejo, D. Calcium‐Dependent Effects of Melatonin Inhibition of Glutamatergic Response in Rat Striatum. Journal of neuroendocrinology. 2001, 13,5, 459-466.

17.       Dröge, W. Oxidative Stress and Aging. Hypoxia. 2003, 191-200.

18.       Reiter, R.J. Oxidative Processes and Antioxidative Defense Mechanisms in the Aging Brain 1. The FASEB journal. 1995, 9,7, 526-533.

19.       Ernster, L.; Dallner, G. Biochemical, Physiological and Medical Aspects of Ubiquinone Function. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 1995, 1271,1, 195-204.

20.       Zhu, Z.-G.; Sun, M.-X.; Zhang, W.-L.; Wang, W.-W.; Jin, Y.-M.; Xie, C.-L. The Efficacy and Safety of Coenzyme Q10 in Parkinson’s Disease: A Meta-Analysis of Randomized Controlled Trials. Neurological Sciences. 2017, 38,2, 215-224.

21.       Hagen, T.M.; Liu, J.; Lykkesfeldt, J.; Wehr, C.M.; Ingersoll, R.T.; Vinarsky, V.; Bartholomew, J.C.; Ames, B.N. Feeding Acetyl-L-Carnitine and Lipoic Acid to Old Rats Significantly Improves Metabolic Function While Decreasing Oxidative Stress. Proceedings of the National Academy of sciences. 2002, 99,4, 1870-1875.

22.       Long, J.; Gao, F.; Tong, L.; Cotman, C.W.; Ames, B.N.; Liu, J. Mitochondrial Decay in the Brains of Old Rats: Ameliorating Effect of Alpha-Lipoic Acid and Acetyl-L-Carnitine. Neurochemical research. 2009, 34,4, 755-763.

23.       Sharma, R.; McMillan, C.R.; Tenn, C.C.; Niles, L.P. Physiological Neuroprotection by Melatonin in a 6-Hydroxydopamine Model of Parkinson’s Disease. Brain research. 2006, 1068,1, 230-236.

24.       Church, F.C. Treatment Options for Motor and Non-Motor Symptoms of Parkinson’s Disease. Biomolecules. 2021, 11,4, 612.

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