This Journal revisits the biochemistry of aging by considering 9 key hallmarks of the aging process, and also serves as a prelude to the next Journal entry which will consider how maintaining muscle mass and functional muscle health is one major antidote to the inevitable biochemical changes imposed by the aging process.
This Journal entry hearkens back to a previous posting about aging entitled Anti-Aging. This writing developed information about the importance of the sirtuin signaling molecules and how they are maintained by the key intracellular molecule nicotinamide adenine dinucleotide, more simply known as NAD+.
As an overview of the biochemistry of aging, the current writing will present conceptual as well as more technical considerations about the complex interrelated processes which regulate aging.
Hallmarks of Aging
In an abstract entitled The Hallmarks of Aging which appeared in June, 2013, in the journal Cell, the authors describe in some technical detail nine biochemical processes which are the determinants of aging. These processes take into account biochemical, genetic, and physiological changes that occur as our years accumulate and pass by.
Here is a very brief description of these 9 interdependent processes of life and healthspan. You can see Associated Reading reference #1, below, to review the entire original article for in-depth biochemical explanations.
Epigenetic Alterations
Epigenetics refers to external modifications to DNA that determine how particular genes are expressed. These alterations do not change the DNA sequence itself. Instead, they affect how genes are expressed to code for all proteins in our biochemistry. All environmental factors and exposures play a large role in these alterations. More years under in our lives means more exposure to environmental factors, and therefore a greater likelihood of alterations in the epigenome.
Loss of Proteostasis
Proteostasis (“protein homeostasis”) refers to proteins in the body being abundant and in their original state. As we age, proteins may get damaged or misfolded, affecting their ability to carry out normal biochemistry. Misfolded proteins can also be toxic. Keep in mind that the word protein includes the host of functional proteins such as enzymes, as well as the more structural proteins such as muscle and collagen based connective tissues. Intracellular and extracellular enzyme activity is the foundational biochemistry of all life. All cellular protein production is coded for by our genes, and is also dependent on the amino acid components acquired from our dietary intake of protein containing foods.
Deregulated Nutrient Sensing
Deregulated nutrient sensing means that body’s chemical mechanisms are not able to detect or use nutrients in a normal fashion. Many related and interconnected nutrient-sensing systems have been the focus of much investigation over the past several decades. One important nutrient sensing system referred to in this writing is the sirtuin family of chemicals which sense NAD+ levels. Other nutrient sensing mechanisms which are well described in nutritional research and writings are the mTOR pathways, which are responsible for sensing of high amino acid concentrations, and AMPK, which senses low-energy states by detecting high levels of ATP precursor molecules.
Mitochondrial Dysfunction
Mitochondria are the powerhouses of the cell and are where most of the cell’s energy gets produced in the form of a molecule known as adenosine triphosphate, or, ATP. As we age, mitochondria become less efficient or may even lose the ability to create ATP altogether. Mitochondria require a specific set of chemicals derived from our nutrient intake to be able to produce robust ATP, and also to be able to carry on with production of new mitochondria. Associated Reading reference #7 gives more information on the consideration of nutrition for mitochondria.
Cellular Senescence
Cellular senescence may be described as an arrest of the cell cycle coupled with a cascade of resultant negative biochemistry processes. When we are young, our cells replicate rapidly. As we age, certain cells lose the ability to divide efficiently and carry out a normal cell cycle of life. These cells often do not die off in the normal programmed cell death process known as apoptosis, but linger on, congesting chemical flow in the intercellular space, and can also secrete damaging molecules into the space between cells.
Stem Cell Exhaustion
Stem cells are our ultimate source of new cells. What is unique about stem cells is their ability to replicate when needed and stop when they are not needed. However, this ability to start or stop the process as required declines with age. Stem cell exhaustion unfolds as a consequence of multiple types of aging-associated damages and likely constitutes one of the ultimate culprits of tissue and organ aging.
Altered Intercellular Communication
Not only do cells degrade over time, but their ability to communicate with each other does as well. This means certain tissues and organs will not get the information they need to function optimally. A prominent aging-associated alteration in intercellular communication is “inflammaging.” This term refers to a smoldering proinflammatory process that accompanies aging in mammals, and is mediated by a variety of well studied inflammatory chemicals known as cytokines. Some well known cytokines are the NfKB transcription factor, the NLRP3 inflammasome, tumor necrosis factor, various interleukins, and interferons.
Genomic Instability
The accumulation of genetic damage throughout life is a common feature of the aging process. The integrity and stability of DNA is continuously challenged by exogenous physical, chemical, and biological agents, as well as by endogenous threats, including DNA replication errors, inflammation, and reactive oxygen species (oxidation). Our DNA is easily damaged, but there are also enzymatic mechanisms in place for DNA repair. This repair isn’t always perfect, and as we age, the damage accumulates. Compromised DNA leads to accelerated aging and disease.
Telomere Shortening
Telomeres are the endcaps on chromosomes which play a vital role in regulating gene expression and the functioning of chromosomes. Telomeres shorten as we age as a result of normal cell division and other inevitable damaging biochemical processes, such as inflammation and oxidation. Critically short telomeres signal the cessation of cell replication. The cell becomes senescent, and fails to propagate.
The authors conclude their writing with some perspectives…”A global view of the nine candidate hallmarks of aging enumerated in this Review suggests three categories: primary hallmarks, antagonistic hallmarks, and integrative hallmarks. The common characteristic of the primary hallmarks is the fact that they are all unequivocally negative…In contrast to the primary hallmarks, antagonistic hallmarks have opposite effects depending on their intensity…A third category comprises the integrative hallmarks—stem cell exhaustion and altered intercellular communication—that directly affect tissue homeostasis and function.”
“Notwithstanding the interconnectedness between all hallmarks, we propose some degree of hierarchical relation between them.”
The authors illustrate how the 9 hallmarks interconnect and interact in a hierarchical relationship.
Phenotype definition – the observable characteristics or traits produced by the interaction of genes with the environment (epigenome).
The authors conclude with these words…”The primary hallmarks could be the initiating triggers whose damaging consequences progressively accumulate with time. The antagonistic hallmarks, being in principle beneficial, become progressively negative in a process that is partly promoted or accelerated by the primary hallmarks. Finally, the integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by tissue homeostatic mechanisms. Because the hallmarks co-occur during aging and are interconnected, understanding their exact causal network is an exciting challenge for future work.”
In further consideration of NAD+
All of the biochemical processes of life listed above require efficient processes of intracellular and intercellular communication. Cellular signaling, and all of the molecular interactions described above, is dependent upon maintenance of NAD+. This molecule engenders mitochondrial health and efficient production of the energy molecule of life, ATP.
Aside from its role in maintaining energy production, NAD+ also plays a role in more than 500 reactions in the body; a list which includes metabolism, aging, gene expression, stress response, and DNA repair. Aging has been well linked to a deficiency of NAD+ and/or insufficient NAD+ for sirtuins which require it to properly perform necessary biochemical processes in the body.
Because NAD+ levels steadily drop with age, the repletion of NAD+ has become a dedicated focus in longevity research. Depletion of NAD+ in the aging process can negatively impact a multitude of core biochemical functions that influence healthspan and degenerative decline.
Sirtuins
Sirtuins are known as silent information regulators (SIR). Technically, these biochemicals are histone deacetylases requiring NAD+ as a signaling coenzyme for their enzymatic activity. Currently there are 7 classes of sirtuins which go by the labels of SIRT1 through SIRT7. These protein molecules play a variety of roles in cellular function, including energy homeostasis, cell cycle regulation, and apoptosis. Sirtuins (SIRT) are also known as NAD+consuming enzymes because NAD+ acts as a SIRT activator.
The particulars of SIRT1 through SIRT7 chemistry were summarized in the earlier Journal writing Some Anti-Aging Biochemistry.
Sirtuin Boosting Foods and Activities
There are particular foods which are known to boost and support sirtuin function. Known as Sirtfoods these foods contain naturally occurring polyphenol compounds that have the potential to activate sirtuins.
Please see Top 20 Sirtfoods/Sirtuin-Activating Foods And Benefits Of Consuming Them which covers some of the nutritional biochemistry of sirtfoods.
Lifestyle activities which support sirtuin activation and expression are exercise, sauna, fasting and maintaining a normal circadian rhythm — while simultaneously avoiding things that deplete your body of NAD+, such as electromagnetic field (EMF) exposure and excessive alcohol consumption.
EMF exposure is one common source of oxidative stress, so it too increases NAD+ consumption. It does this by activating an important DNA repairing enzyme known as PARP (poly ADP ribose polymerase). PARP activity is linked to enhanced lifespan. Each time PARP is activated, it uses up 150 molecules of NAD+. Hence, reducing EMF exposure can also be an important strategy to preserve and protect NAD+ levels for its other functions.
Your body also uses up NAD+ to detoxify alcohol, so if nightly drinking is part of your routine, consider reducing or stopping consumption.
If one is allowing daily EMF exposure (computers, cell phones, etc.) and is consuming any amount of alcohol, then one cannot ignore countermeasures to reduce, mitigate and improve upon the negative aging effects which EMF and alcohol impose upon our chemistry.
Aside from foods and lifestyle practices which enhance NAD+ and sirtuin activity there are nutritional supplements, such as nicotinamide mononucleotide (NMN), which boost NAD+.
A New NAD+ Boosting Supplement and other Sirtuin Support Supplements
NMN is the most efficient and effective supplement booster of NAD+ which is known. This molecule is the direct precursor of NAD+ production in the mitochondria.
NAD+ has never been stabilized to be taken as a stand alone supplement, but its levels in our biochemistry can be supported and elevated by taking its direct precursor NMN.
Designs for Health now offers a stabilized and deliverable NMN formulation in its impressive product line. Containing 50 servings per bottle, Liposomal NMN Synergy has been formulated to contain 50 mg of nicotinamide mononucleotide (NMN) and 50 mg of trimethylglycine (TMG) per serving to support healthy aging and cellular function.
This liquid is dispensed from its bottle via a simple pump mechanism. Used once or twice daily, its benefits on enhanced NAD+ and sirtuin chemistry will be noticed as aging processes are mitigated. Typical improvements noticed within a month of administration are improved energy, mental clarity, and overall resilience.
The recommended use is to take 1 mL (approximately 2 pumps) and hold in mouth for 30 seconds before swallowing. Take on an empty stomach at least 10 minutes before meals. It may be stirred into a small amount of water.
There are a number of nutrients which have been researched and are known to influence sirtuins in a beneficial way. The nutritional supplements listed below are known to assist sirtuin function and other aspects of anti-aging biochemistry. These links will take you to specific Designs for Health supplements on the website store.
- vitamin D
- melatonin
- omega 3 fatty acids
- zinc
- resveratrol
- quercetin
- EGCG
- magnesium
- vitamin B3 (niacin)
- amino acids
New antiaging formulations
Designs for Health has recently introduced 2 new formulations which help support aging cells and overall biochemistry. These compounds help address a number of facets of the 9 processes of healthspan and sirtuin function mentioned above.
- Senolytic Synergy…This compound is formulated to enhance overall cellular health and support healthy aging. It contains a synergistic blend of well-researched ingredients that help attenuate cellular aging by supporting apoptosis to promote senescent cell clearance and a healthy inflammatory response. Each two-capsule serving provides 200 mg each of curcuminoid powder, quercetin, and red grape powder, along with 100 mg each of the fisetin and Senactiv (a proprietary blend of Panax notoginseng and Rosa canina). Fisetin, a unique flavonoid that supports senescent cell apoptosis, is a bioactive compound found in many fruits and vegetables that has shown anti‑inflammatory and chemopreventive potential, and more recently, it has demonstrated senolytic activity, helping to overcome resistance of senescent cells to apoptosis.
- NRF2 Modulator…This product was formulated to help activate the Nrf2 pathway, which is the main regulator of the body’s endogenous defense against oxidative stress and associated damage. This pathway regulates the production of important molecules that impart antioxidant activity, such as glutathione. It also regulates the production of detoxification enzymes and modulates the inflammatory response. NRF2 Modulator supports the activation of this pathway to promote oxidation/reduction (redox) balance and a healthy inflammatory response. Ingredients include stabilized curcuminoid complex, red grape powder, quercetin, olive fruit complex, trans-Pterostilbene, and vitamin E isomers. Pterostilbene is a naturally occurring phenolic compound and analog of resveratrol that has demonstrated cytotoxic, cytokine-inhibiting, and antioxidant properties. In cell and animal studies, pterostilbene has been shown to activate the Nrf2 pathway to promote transcription of specialized antioxidant genes.
- Mito-NR…this supplement is formulated to support cellular energy production, cellular repair, and healthy aging. This formula contains clinically relevant amounts of Niagen, a form of nicotinamide riboside chloride (NR), coenzyme Q10 (CoQ10), and geranylgeraniol (GG). NR is a pyridine nucleoside form of vitamin B3 (niacin) and a building block of nicotinamide adenine dinucleotide (NAD+). Mito‐NR provides 300 mg of nicotinamide riboside chloride as Niagen, 200 mg of CoQ10, and 50 mg of GG as GG‐Gold that support energy production using multiple biochemical mechanisms; therefore, they may have synergistic effects on energy production. They may also support mitochondrial health and healthy aging. Mito‐NR may be ideal for individuals concerned with age‐related illnesses, those in need of cellular energy support, and those who may require support for healthy mitochondrial function.
- Cell Guard-NR…this supplement is formulated to support cellular repair, antioxidative status, and healthy aging. This formula contains clinically relevant amounts of Niagen, a form of nicotinamide riboside chloride (NR), resveratrol as Veri‐te, and pterostilbene. NR is a pyridine nucleoside form of vitamin B3 (niacin) and is a building block of nicotinamide adenine dinucleotide (NAD+). CellGuard‐NR provides 300 mg of nicotinamide riboside chloride as Niagen, 200 mg of resveratrol as Veri‐te, and 50 mg of pterostilbene. Together, these nutrients help support a healthy cell cycle, a healthy response to oxidative stress, cellular repair, and healthy aging. CellGuard‐NR may be ideal for individuals concerned with healthy aging, those who need support for antioxidative status, and those who may require support for healthy cellular repair, function, and regeneration.
Conclusion
A vital tissue to maintain for health and functional longevity is muscle, and this consideration includes all 3 types of muscle: skeletal muscle, smooth muscle, and cardiac muscle. While these 3 types of muscle are under different types of neurological control, their nutritional, biochemical, and lifestyle influences are the same.
As with all of the trillions of cells in the body, consideration of muscle tissue health and vitality incorporates all of the biochemical processes written about above. If one can maintain muscle health via exercise and nutritional chemistry, then is is certain that one will also be maintaining the health of all organs.
The next Journal writing will consider the many benefits of muscle health and how we can maintain and improve muscle health as we age.
Signing off from Crestone and Beyond
Associated Reading
- The Hallmarks of Aging…the original article in the journal Cell from which the opening abstract and summary comments above was developed.
- Lifespan: Why We Age–and Why We Don’t Have To…a book by geneticist David Sinclair, Ph.D., who researches in his Harvard lab. This book goes into NAD+ and the sirtuin pathways, and the many processes which support healthy aging.
- The Empowering Neurologist–David Perlmutter M.D., and Dr. David Sinclair…an informative one hour interview from 1-24-21 which covers many aspects of anti-aging wisdom.
- Therapeutic potential of NAD-boosting molecules: the in-vivo evidence…a technical writing from 3-6-19 authored by David Sinclair, Ph.D., and associates which appeared in Cell Metabolism. This article is dense, but informative.
- Top Ten Sirtuin Foods for Good Health…another listing of sirtfoods which you can peruse and study and come up with your favorites. You can also explore some of the other sirtfoods which may not be common in your diet.
- Alpha-Ketoglutarate: Physiological Functions and Applications…this is a nice technical summary of the effects of AKG on bone-collagen-muscle health, immune system health, and aging health. Designs for Health features 2 premier amino acid formulations which contain AKG…Amino Acid Supreme powder and Amino Acid Synergy capsules.
- The Ketogenic Diet…a writing on this website about the ketogenic diet. One benefit of keto dieting and intermittent fasting is sirtuin activation.
- Minding your Mitochondria…a writing on this website about the importance of mitochondrial health and maintenance.
- Minding your Methylation…a writing on this website about the importance of an overarching aspect of our biochemistry.
- Your Personal Genetic Analysis…a writing on this website which explains a good bit about genetics, such as the epigenome and epigenetic influences.
- Programmed Cell Death…a collection of technical articles which cover the chemistry of apoptosis. The term apoptosis is derived from Greek etymology and means “falling off.” The term refers to how leaves on a plant are programmed to fall during the autumnal to winter seasonal transition.
- Association of Telomere Length With Risk of Disease and Mortality…a report in the January 18, 2022 JAMA. Reduced leukocyte telomere length (LTL) was associated with 8% increased overall mortality, 9%cardiovascular, 40% respiratory, 26% digestive, 51% musculoskeletal, and 15% COVID-19 mortality, but not cancer-related mortality. 214 disorders were overrepresented, 37 underrepresented with shorter LTL. Malignant tumors, esophageal cancer, and lymphoid and myeloid leukemia were more common with shorter LTL, whereas brain cancer and melanoma less prevalent.
- Cellular Senescence and Adrenal Health…a short reading which explores the relationship between adrenal gland health and aging.