Abstract
Whether you live in the blue zone, looking to improve your health parameters , galloping that longevity supplement or perusing any other biohacking technology to up your longevity game, until you are revitalising & rejuvenating your cells, you cannot move ahead in your peak health performance.
Cells inside our body, 37 trillion of them, lay the foundation for longevity & are considered to be building blocks for keeping your organs & tissues in proper order. In fact, cellular homeostasis at system biology level can up your longevity journey.
To really understand the biological mechanisms underlying aging, you need to go beyond blood biomarkers/plasma level investigations/circulatory toxins & metabolic byproducts & identify dysregulation in cellular functions.
Our health is a direct function of the health of our cells. Our cells perform various functions including sensing extracellular matrix, stimulating various actions such as producing nitric oxide, promoting mitochondria biogenesis, mitochondria efficiency, protein synthesis( ability of our cells to make, fold, deliver, transport or degrade various proteins), repair signalling, stem cell regenerative signalling, autophagy controlling oxidative stress & production of free radicals, regulation of telomeres & more. When our cells get damaged or dysfunctional due to inflammation, external insults & provocative agents or cannot be repaired or replaced due to lack of cellular signalling cascades, it leads to something referred to as cellular senescence. This could lead to progressive decline in vital cellular functions & onset of various age related diseases including cardiovascular diseases, dementia & more.
The following paragraphs give you a fresh perspective on cellular events that you should consider evaluating to reduce your biological age, rather than just getting blood works done/following generic nutrition/supplement interventions.
The hallmarks of aging
Over years of research, scientists & researchers have identified 8 cellular events, also referred to as hallmarks of aging, that could make your age faster & accelerate the onset of age related diseases. These hallmarks are related to specific events/ functions performed by the cells. With occurrence of specific controllable events, our cells decline in essential functions & our biology encounters a lightening up/ upregulation level of specific pathways that leads to cellular senescence, cellular decay & accelerated aging.
The science related to & hallmarks of accelerated aging is described below
- Mitochondria Dysfunction
The external provocative agents & insults, the outcome of interaction between the various food substrates & your microbiome, environmental toxins, social interactions, could lead to systemic inflammation & oxidative stress. This destroys mitochondria of affected cells & makes mitochondria produce reactive oxidative species(ROS) that damages DNA, RNA & protein, causing genomic instability. This is also said to be the underlying cause of cancer.
Nitric oxide plays an important role in promoting mitochondria biogenesis( increasing the number of mitochondria per cell) & improving mitochondria efficiency as it controls the electron transport chain & flow of electron to inner mitochondria membrane, enabling mitochondria to do its job, promoting longevity & slowing down biological aging.
Nitric oxide once produced, in case of intermittent fasting, caloric restriction, leads to activation of second messenger cycle GMP that activates PGC-1 alpha, the master regulator of mitochondria to stimulate mitochondrial biogenesis.
Apart from nitric oxide, various molecules in the food we eat that could stimulate PGC-1 alpha & lead to mitochondria biogenesis & promote bioenergetics include NAD, Trimethylglycine(TMG), Ursolic acid, Dietary nicotine & more.
It is very vital to understand the interaction between foods having these molecules & your microbiome.
2. Telomere Regulation
Cell division is a normal process of cell growth cycle & DNA replication where parent cells are divided into multiple cells, creating new cells for growth & repair. With DNA replication at every stage, telomeres- the protein structures at both ends of chromosomes start becoming shorter. This is referred to as telomere shortening & is a hall mark of mortality & age related diseases. You can regulate & prevent telomere shortening by activating an enzyme Telomerase which needs nitric oxide as a signalling molecule. Therefore your endothelial nitric oxide synthase(eNOS) should be constitutively expressed & coupled with endothelial cells to produce nitric oxide that regulates your telomeres. Other factors that could lead to telomere shortening include gut derived harmful metabolite phenylacetylglutamine(PAG) & high homocysteine levels. High homocysteine levels lead to overexpression of asymmetric dimethyl arginine(ADMA) which suppresses nitric oxide production, leading to underexpression of telomerase & causing telomere shortening. It has also been found that there is an inverse relationship between periodontal disease & telomere length, further underscoring the role of nitric oxide & oral microbiome in aging.
3. Decline in cellular proteostasis
Our cells play important functions in protein synthesis. This includes the way our cells make, fold, deliver, transports & degrade excess protein. Any disruption in cellular proteostasis could lead to misfolded protein, cellular stress & unfolded protein response which could result in protein not reaching the specific organelle, leading to cellular decay & dysfunction, immune system functioning & accelerated aging.
4. Decline in nutrient sensing
Our cells need fuel to perform various tasks & keep the body running as a well oiled machine.The food we eat has a lot of nutrients that need to be carried to cells through specific pathways such as AMPK, mTOR, sirtuins & more. These help cells metabolise nutrients appropriately. With age, these specific pathways tend to decline, resulting in disruption in sensing mechanisms. Some of the signs of this decline in nutrient sensing includes low grade chronic inflammation, insulin resistance(again outcome of chronic inflammation), This may also lead to cell death.
Nitric oxide, the essential signalling molecule, modulates the activity of these pathways & growth factors- AMPK, mTOR & IGF-1 which could inhibit inflammation & prevent insulin resistance. Nitric oxide is the signalling molecule that signals protein GLUT 4 to go to the cell membrane, bind to glucose, clear it from circulation & transport it to cells for energy or storage.
Measuring the level of nitric oxide production is key to regulating the nutrient sensing signals & pathways.
5. Cellular Sensenence
Your microbiome performs various vital functions & interacts with food substrates that could lead to either flow of essential nutrients or toxins/harmful metabolic byproducts that could trigger chronic inflammation & oxidative stress. This makes cells age rapidly & reduces/inhibits the ability of cells to repair & replace dysfunctional cells & to replicate & produce more cells. Over time, our cells cease to divide & enter stage referred to as cellular senescence.
These senescent cells release chemicals that stimulate inflammation in surrounding cells. This cascading effect results in a weakened immune system & your body does not respond appropriately to illness & other onslaughts.
The cellular senescence leads to rapid & accelerated biological aging at cellular level & is connected with various age related conditions.
6. Stem cell signalling
Our daily choices are wearing ourselves out. As a result our cells are under tremendous stress & could become dysfunctional. It is the job of our stem cells to repair & replace dysfunctional cells. Without stem cells, we cannot repair our cells, it leads to cellular decline & even apoptosis( programmed cell death). We have stem cells in our bone marrow, circulating blood & fat cells. As we get older, there are less number of stem cells in bone marrow & circulating blood & the major reservoir for stem cells is fat cells.
During the time of repair, we need to mobilise & differentiate our stem cells for which our body must be producing nitric oxide. Nitric oxide is a signal for stem cells to differentiate & go to the site of injury or repair to repair & replace dysfunctional cells. Besides, improper nutrition choices could lead to production of toxins that get stored in fat cells. This renders stem cells ineffective & interfere with their repair functions
Some of the signals that your stem cells are not working to the best of their abilities or have become ineffective could be fatigue & compromised immune function
7. Intercellular communication
The cells must be able to communicate with each other to maintain cellular homeostasis & regulate gene expression levels. This regulates various metabolic functions including glucose metabolism, cholesterol metabolism, sleep, mood, immunity
When the cells cease to communicate, as generally happens when we age, the cells lose their ability to regulate these functions. Some of the indications of disruption in cellular communication include fatigue, weakness & slow wound healing.
Nitric oxide(NO) plays an important role in facilitating intercellular signalling. NO can diffuse across cell membranes & allow paracrine & autocrine signalling. In fact, NO is regarded as a hormone & plays a key role in cellular communication at system biology level & have systemic effects on all organs, tissues & cells.
Stimulating nitric oxide production via both endothelial nitric oxide synthase & oral microbiome pathways could regulate intercellular communication & genes expression levels.
8.Maintaining cell structure
Our cells have phospholipid bilayer- cell membrane & it needs lipids , cholesterol & healthy fats to maintain its structure, architecture & fluidity. This fluidity allows for intracellular signaling,sense extracellular matrix, binds to receptors & turns on protein & genes to perform various biochemical functions. One of the important nutrients that helps maintain cell structure & fluidity is pentadecanoic acid-C15, an odd chain saturated fatty acid. Every cell including red blood cells need this saturated fatty acid to maintain the cell structure. We need to maintain 0.4% of C15 as % of total saturated fatty acid in the cells.
When we are C15 deficient, red blood cells become weak & they are engulfed by kupffer cells( macrophages in the liver) & the corpses left behind are iron. This act of macrophages over time leads to iron overload which can harm liver cells, lead to liver dysfunction, fat accumulation, NAFLD & cellular fragility syndrome. This iron overload could have a spillover effect on other body organs including pancreas, leading to type 2 diabetes. Iron also reacts with lipid peroxidation in the fragile cells to cause oxidative stress & cell death called- ferroptosis.
Another important aspect is that the odd chain saturated fatty acids are metabolised with 2 carbon in a row 15→13→11→9→7 & so on. Finally C15 is metabolised into propionic acid which secretes GLP-1 & PPY, promoting satiety & glucose homeostasis
C15 improves the cell membrane strength by 80%, clear the damaged zombie cells by activating AMPK, inhibits mTOR, restores mitochondrial function, lowers pro-inflammatory cytokines, and promotes beneficial gut microbiome functions
9.Microbiome driven metabolic dysfunction
Our cells (including microbial cells) have enzymes & proteins that speed up & execute various biochemical functions necessary for various life processes. For instance, signalling molecules (nitric oxide) within the cells could activate a protein GLUT4 that clears the glucose from the circulation & helps in maintaining metabolic homeostasis.
High sugary & ultra processed foods are sticky. They stick to protein & enzymes, prevents them from doing their job & makes them dysfunctional. This results in metabolic abnormalities as observed in type 2 diabetes, obesity & other metabolic diseases.
Another important aspect is triglycerides(TG). Triglycerides are a type of lipid found in blood & even excess calories we consume are stored as triglycerides. Instead of integrating into cell membrane ,TG are stored in lipid droplets in the cytoplasm that acts as cellular storage depots to meet energy needs, regulate lipid metabolism, protects against lipid toxicity that can damage cell membrane, acts as lipid precursors for synthesis of new membranes & modulate cellular signalling & stress response. Lipid droplets reduce unfolded protein response(UPR), cellular stress, manage endoplasmic reticulum, and protect cells from oxidative damage. These lipid droplets(LD) also play a role in protein storage, synthesis & turnover & interacts with other organisms such as Mitochondria to facilitate lipid & protein transfer.
LD also plays an important role in reducing lipid peroxidation by sequestering polyunsaturated fatty acids away from cell membranes, reducing harmful oxidation & preventing cells from oxidative stress & maintaining cellular homeostasis.
The gut microbiome controls the lethal breakdown of lipid droplets, thereby regulating lipid metabolism by releasing various metabolites such as butyrate.
Gut microbial dysbiosis could lead to overexpression of inflammatory pathways & metabolites such as TMAO, LPS, P-cresol, PhenylacetylGlutamine, Uric Acid, high bile acid & more which could lead to fat accumulation, liver dysfunction & high TG levels. On the other hand, when the gut is balanced & promoting beneficial functions, it could secrete butyrate that leads to fatty acid oxidation & reduces triglycerides levels.
Your oral microbiome could also reduce TG levels by stimulating the production of nitric oxide.
Although eliminating sugar could be a good starting point to improve our metabolic health & reducing triglyceride levels, you need to measure your system biology to understand various dysregulations in biochemical reactions that may be elevating your triglyceride levels.
Final Words
If you really want to promote longevity & reduce your biological age, you need to reinstate your cellular functions.Any insights from the routine diagnostic tests cannot deep dive into specific dysregulation in cellular functions that is causing you age faster. Any of the solutions that are assessing your biological age based on blood works or DNA methylation tests are complete waste of money.
We at Genefitletics measures your biochemical functions at cellular level to identify specific pathways which are being upregulated or downregulated leading to dysregulation in cellular homeostasis, causing cellular senescence & progressive decline in cellular functions & then deliver data driven nutritional therapeutics interventions that slow down & reduce your biological age.
More details here: http://genefitletics.com/agegorithm/
Citations
https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.1067647/full
https://academic.oup.com/eurheartj/article/44/Supplement_2/ehad655.2052/7391414
Leave a Reply