This post aims to introduce the basic biology of aging in various simple and complex organisms, including humans.
We must understand the intricate molecular processes that evolve in our bodies as we grow older to live longer and age better.
It is fascinating from years in medical school to appreciate the reproduction process in mammals, especially humans. I am looking at fertilization and embryogenesis with the intricate and delicately guided change process from a newly fertilized single cell and then two-cell embryo developing to a fetus. Intriguing is that the same cells invariably differentiate into bones, cartilage, hair, and muscles that form different organs and then a baby.
As the baby grows, the cells divide and undergo differentiation under genetic guidance. The changes are profoundly influenced by the environment, sustaining and maintaining growth, hence contributing to life's long-term survival. It is intriguing to know that this growth process also contributes to the aging process.
There must be an underlying process responsible for these very intricate changes that result from the genetic blueprint that was 'patched together' from two genetically different individuals as mother and father? The quest to find answers prompted the search for a structured understanding of the biological basis for aging.
Throughout history, aging has been a battle that human beings have had to fight even when they know they may not win. There has been a giant leap in understanding the universal relationship between matter and energy about health over the last decade or so. Scientists also understood the aging process better through an inclusive and intricate understanding of universal energy (including the influence of its effects!).
Understanding the biological and molecular mechanisms that drive cellular transformation and growth. However, though aging cannot be stopped, it can influence adverse factors.
This influence and control are possible by manipulating the microcosmic environment from genetics to cell metabolism and growth through lifestyle changes that hinge on the diet, exercise, and alignment to universal energy.
Aging, by definition, is said to be a progressive decline in the function of the cellular components of tissues, organs, and an organism over time, that eventually lead to senescence (a progressive decline in divisive power of cells) and death.
This blog post expounds on a range of factors that influence aging simplistic yet organized. It also highlights it as a multifactorial process, controlled by a genetic blueprint, inveigled by microcosmic metabolic and environmental factors. Hence, the aging process is a confluence of biology and evolution because of this complexity.
For any meaningful insight into the process of aging, it is essential to understand the fundamental concepts, including the structural and functional aspects of the genome (blueprint), which includes the gene with DNA and its complex structure and relationship with the cell.
Genes are the genetic code or blueprint generated by combining traits from both parents. It contains the master sheet of every information necessary for living cells to survive and reproduce.
In eukaryotic organisms and humans, genes contain DNA, where a particular sequence determines the functional expression of the gene they code. The function is conducted by proteins.
THE BLUEPRINT, 'THE ZIPPER' – DNA
Genes are made up of 'chips' on the strand or chain of the macromolecule in our chromosome known as De-oxy ribonucleic acid or DNA.
The DNA molecule consists of two complementary strands, one from each parent, that wind around each other like a twisted ladder (called helix). These strands are antiparallel and locked like a 'zipper.' This double strand allows the cell to make two new, identical copies by 'reading' and copying each strand separately in a process known as replication.
The structure of these strands comprises a backbone of the alternating macromolecules called nucleotides. Each nucleotide consists of a nitrogenous base and molecules of the sugar deoxyribose and a phosphate group. There are four nitrogenous bases in human DNA, Guanine, Cytosine, Thymine, and Adenosine, represented as GCTA.
It is crucial to understand that every function, regulatory or otherwise, and most structural components of the human cell, tissue, and organ, are composed of proteins.
Proteins are the ultimate complex configuration of a chain of amino acids, which in their simplest form are known as peptides and polypeptides depending on their length. So, a simple polypeptide chain consists of linked amino acids in a sequence determined by genes.
The genetic codes (or gene), which are responsible for synthesizing any polypeptide chain and protein needed for the protein-mediated activity or structure, comprise a consecutive strand of three complementary bases in the region of DNA, each called a codon. The codon determines the program to generate a specific amino acid.
Hence, the amino acid sequence of every protein is synthesized by codons of DNA, and the individual's genetic blueprint is transferred during fertilization and propagated with growth. When the body is growing by regenerating cells or repairing a tissue, the new cells are made by cell division, which involves replicating the exact copy of each DNA of the original cell to form daughter cells.
It is a process constantly going on repeatedly as cells divide to regenerate. It is performed with a high degree of accuracy, fidelity, and efficiency and was the same process that the embryo utilized to grow in utero.
As mentioned previously, the body's physiological functions are affected by various proteins, either as membrane components or enzymes; hence, proteins participate in the body's structural and functional microcosm.
UNDERSTANDING POLYPEPTIDES & PROTEINS
Proteins are a complex coiled chain of amino acids that are products of digestion from our food. The human body uses twenty amino acids, some we can make in our body, but most come from the diet. The amino acids are chemically linked in polypeptides chains when they are straight (like insulin) but become proteins when they are exceptionally long and coil to secondary and tertiary forms.
It should be noted that these conformational changes in the polypeptide chains to form proteins are responsible for all physiological and biological functions of proteins. A good example is oxygen transportation by the iron attached to a protein molecule known as globulin found in hemoglobin, responsible for maintaining all mammalian life on our planet.
Earlier, we alluded that the amino acid sequence of every protein is synthesized using codes on the DNA segments of our genome called codons. Through a process known as transcription, the codes are copied into another type of macromolecule known as messenger Ribonucleic acid mRNA, which translates the codes/command from the DNA. mRNA carries the copy across the nuclear membrane to the cell's cytoplasm.
In the cytoplasm, another type of RNA, the transfer RNA tRNA, also produced in the nucleus but functionally in the cytoplasm, acts as 'scanners' transcribing the codons from the mRNA copy of the genetic code to form a sequence of amino acids in a continual process.
The result is the stacking of the amino acid in the sequence determined by the gene or DNA codons and thus forming polypeptides, the primary form of proteins.
It is important to note that the genetically determined sequence of the amino acid chains must be perfect for functional integrity. That is how faithful it must be to avoid disorders. An example is that just a breach leading to just one substitution of an amino acid in the beta chain of the globulin in hemoglobin causes a lifetime of Sickle cell disorders.
The polypeptides formed from translation must be modified with the help of another RNA called ribosomal RNA into the 'folded' coils of secondary, tertiary, or quaternary structure to become a structural or functional unit.
The color shade of our skin to the function of most tissues like hemoglobin in red blood cells, the secretion of growth hormone stimulating hormone, and other factors that control the phenotype or the external look are determined using these complex proteins.
The conclusion from the above is that humans and animals' unique characteristic, nature, function, and form is encoded in their genes. These delicately woven and intricate processes of translating the genetic code into expressed structural or functional manifestation ensure perfectly executed.
However, science has discovered that 'mistakes' or mutations happen, and environmental factors also affect the process. Nevertheless, it is a scientific highlight that the intricacy of genetic replication understandably calls for the maintenance of the structural integrity of the DNA blueprint itself using self-generated internal repair enzymes called DNA polymerases.
It is easy to imagine that during a lifetime of living, injuries, and repair of natural 'wear and tear,' this process continuously continues while maintaining significant replicative fidelity.
During regeneration and repair for maintenance of tissues, the average human cell can only divide by replication of the double-strand DNA into two copies and daughter cells about 40-80 times before it 'wears out' depending on tissue type.
Blood cells and epithelial cells of our skin and lining internal organs like intestines, reproductive organs, and urinary tract are constantly multiplying because of the high frequency of use, leading to high 'wear and tear.' Hence, they have the shortest span.
The regeneration process is supposed to repair and restore every tissue to its original state, thus causing no visible change. However, the limited capacity of cells to continue to divide beyond a limit causes cells to degenerate, deteriorate, and disintegrate after their programmed 'limit.'
Though there is significant fidelity in the replicative process of cell division, mutations, when they occur, are fixed by intricate innate mechanisms, as mentioned earlier, or 'overlooked' if deemed not detrimental.
However, over time, this gradual accumulation of unrepaired mutations leads to diverse types of alteration of DNA sequences, like a stretch of codes being added by mistake to one daughter cell during the replication process influencing the expression of genes, which invariably lead to wrong protein formation, altered function, and ultimately leading to cell death or apoptosis. It could also be just a point mutation etc.
The DNA damage theory of aging hence postulates that the accumulation of DNA alterations and 'mistakes' during replication results in the loss of functional fidelity of proteins hence the organelles of individual cells. This damage could also affect the nuclear genome and mitochondrial DNA.
So, in summary, failure of genomic fidelity to replicate the genetic material or fix errors introduced by genotoxic agents from within or from the environment may alter gene expression and create aberrant protein products. These changes, in turn, cumulatively cause cells to senesce and ultimately die.
It is interesting to note that most of the disorders associated with aging, especially the syndromes of premature aging like Hutchinson-Gilford Progeria Syndrome, Werner's syndrome, and many orders, are linked to defects in the maintenance of this structural integrity of the DNA. It gives credence to the importance of the fidelity of replication and DNA maintenance/repair has on the process of aging.
Furthermore, other chronic illnesses like Diabetes Mellitus, Hypertension, Heart disorders, Cancers, and neurodegenerative disease have been linked to an abnormality in the structural or functional proteins related to genetic aberration from the aging process.
Simply put; therefore, a healthy lifespan in aging is determined by the net result of the limited regenerative replicative ability of cells in the tissues and organs with the rate of accumulation of dysfunctional proteins and dead cells — the regeneration - degenerations ratio.
The scientific or laboratory study of aging, healthspan, and senescence is extremely limited in the human population for obvious reasons of time and ethics. However, research is currently active in various laboratories using model organisms chosen for biological simplicity. More importantly, they can be studied over relatively short periods, like the budding yeast- Saccharomyces cerevisiae and the worm Caenorhabditis elegans, as well as Mice.
These have essential correlations with human DNA and are demonstrated by experimental gene sequencing transcriptional fidelity. Like in humans, they also reveal different genes that facilitate DNA repair, genomic stability, growth factor signaling, and gene silencing, which are fundamental determinants of life span in the species.
Similar mechanisms have evolved in these organisms, which protect against the barrage of damages inflicted on the genome, and the genetic changes have also been identified and studied by Fluorescent in situ hybridization (FISH).
THE STOP-END 'CHECK' FOR THE ZIPPER – THE TELOMERE
The insights gained in studying these organisms have been profound; for instance, it was discovered that there is a noncoding sequence that formats the end of DNA in chromosomes known as Telomere.
These noncoding areas or Telomere has been found to function as buffers that protect the DNA from being damaged during replication (just like the stopper end of a pants zipper prevents lousy alignment). The discovery earned the 2009 Nobel Prize for Medicine to the duo of Jack Szostak and Elizabeth Blackburn.
Therefore, we can explain the limitation in the number of the replicative capacity of cells based on the above research, which showed that following each replication and cell division, the length of Telomere gets shorter. Hence, it shortens till the cell loses its protective buffer over time. Therefore, the number of times any given cell replicates with high fidelity before degeneration is limited by the length of its Telomere.
This limit in the replicative ability of cells related to their Telomere length is called the Haylock limit. Hence the conclusion that cellular maintenance of telomere length plays a role in the life span of cells and signaling of cellular senescence can be extrapolated to tissues, organs, and the body.
It is now established that accumulation of DNA alterations and repair influencing genomic stability and age-dependent telomere shortening are associated factors in determining organisms' life span and aging.
In addition, scientists also determined that the shortening of Telomere triggers the activity of a regulator gene known as p53, which affects other cellular functions, including mitochondrial function, slowing the cells' metabolism, leading to functional, cognitive, and physical decline.
There is the suggestion that this action of the p53 gene regulator is protective because doing this also gives the DNA time to repair itself and hence a way to avoid cancer.
The subsequent finding is that a repair DNA polymerase enzyme influences sustenance of the length of the Telomere is known as telomerase which keeps repairing and replenishing telomeres is remarkable. The enzyme telomerase repairs the Telomere after it is clipped during cell division.
Scientists have also discovered that the telomerase enzyme is highly expressed by stem cells, giving them the capacity to maintain an exceptionally long and almost immortal life span. Unfortunately, another subset of cells with a similar ability to use high telomerase activity in cancer cells. (Which is why cancer cells are immortal)
Therefore, we can begin to appreciate why cancer is a disease that begins to show up at the end of our lifespan when p53 and other genes are trying to influence the expression of the telomerase enzyme for telomere repair.
LONGEVITY AND ITS 'DEMONS'
Therefore, the multiple levels of genetic control involved in the expression, suppression, and modulation of telomerase activity, on the one hand, direct the differentiation and growth of cells towards longevity, and on the other hand, avoid cancer formation. These systems understandably begin to malfunction as they get overworked with time.
Hence over time, with a continuous cycle of repair and regeneration leading to DNA replications and repair with telomerase depletion, the genome becomes increasingly vulnerable to the factors that affect its fidelity and integrity leading to other dysfunctional states or senescence.
The organization of DNA within the nucleus is made possible by another set of proteins called histones; the strands bearing codons are wrapped around specific histones to form nucleosomes and then chromosomes.
The N- terminal of the primary polypeptide of histone proteins becomes vulnerable to various modification forms by environmental factors, including methylation, acetylation, and ubiquitination. These modifications are caused by multiple factors, from chemicals and toxins to radiation. These factors, outside of the genetic code and process, are hence referred to as 'epigenetic' (outside of the gene).
Some of these epigenetic modifications invariably become responsible for numerous alterations to gene expression that ultimately lead to senescence, growth regression, and even cell arrest or apoptosis. These exact mechanisms also create interference in regulating, expressing, or repressing growth genes, leading to chronic diseases and oncogenic aberrations on the genome that lead to tumorigenesis or cancer.
It was mentioned earlier that evidence suggests that cells have specific DNA methyltransferases and polymerases that function continuously during replication to repair alterations and stabilize the genome. The genomic repair process is more vigorous in early life. Their efficiency begins to dwindle with age, allowing adverse factors such as nutritional and oxidative stress and external factors like toxic radiation to alter the balance between disruption and repair.
The net result is unwanted epigenetic modifications that accumulate over time, leading to senescence, apoptosis, and degeneration (Aging with disease)
STEM CELLS TO THE RESCUE
As can be deduced from the above, it is also consensus that most metabolic and degenerative disorders and cancer associated with older age are the direct results of the accumulated mutation causing epigenetic alterations and the inability to regulate the expression of oncogenes and telomerase during cell division and growth.
One group of cells that brought the attention of research scientists to this phenomenon is stem cells. They are versatile pluripotent cells responsible for differentiation to other cells during embryonic development but continue this function in adulthood as the source of regeneration and repair of damaged tissue.
One hypothesis predicted that stem-cell depletion in mitotically active tissues leads to many physical expressions (phenotype) associated with aging. This hypothesis becomes attractive because it provides a potential synthesis explaining all of the proposed causes of age-associated cell loss and tissue degeneration.
These changes, including DNA damage, telomere shortening, mitochondrial dysfunction, and reactive oxygen species, could converge to lead to widespread stem-cell depletion as an organism ages.
THE PROTEIN PRODUCTION LINE
Another facet to the progressive alteration in the genomic expression involves the genetic translation and assembly of intracellular proteomes, which is another tightly controlled process.
One in which DNA transcription within the nucleus leads to the translation by different RNAs to the synthesis of proteins in the cytoplasm, where they are then folded into their tertiary and quaternary functional or structural state within the cell akin to a manufacturing production line from raw materials to packaging.
This tightly controlled, efficient mechanism can also be disrupted by epigenomic instability or alteration.
Hence, it is understandable that age-related degeneration that causes metabolic syndromes that lead to Diabetes and neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's disease are due to resultant changes in the genetic control of energy systems and protein synthesis within the cell.
These aberrations in RNA translation, through modification to the management of protein folding and assembly in the cells, including neuronal cells, lead to abnormal aggregation in the cytoplasm of cells, causing the degeneration within cells and the formation of amyloid plaques neuronal cells.
This process was studied under a controlled environment using C. Elegans worm identified regulatory genes called MOAG 4 (Modifier of protein aggregation). The bioidentical genes in human Serf 1A and Serf 2 have also been identified. It is the vision of medical scientists that the inactivation of the expression of these genes would protect our brain against these disorders.
Most of my blog posts will be devoted to knowledge that seeks answers to questions and digs deeper into understanding factors involved in aging.
The above post attempts to excite the imagination simplistically to the fundamental cellular mechanisms working in the background to keep our tissues in optimal health and the factors that continually influence the efficiency and fidelity of these mechanisms.
It deliberately avoided some technical details and biology.
However, it is a marvel to visualize something as little as the sperm cell as it fertilizes the equally small egg by a process that microscopically is fantastic. The resulting fertilized embryo undergoes a metamorphosis that may seem surreal from thence.
It is now an orchestrated, well-choreographed and collaborative process based on a blueprint of the DNA and the 'contractor' readers that invariably direct the 'architects' in the formation of the building blocks or specific proteins.
These proteins form the structure and maintain the function from a fetus to adulthood.
My professional life is profoundly influenced by the restless curiosity devoted to understanding the imperatives and details of this process.
Holistic as it may, from the quantum energy flux of the atoms to the architectural spiritual beauty of our body and all the intricate mechanisms that keep it whole. Sitting on the tripod of Mind, Spirit, and body, all under the influence of another tripod of Mindset, Mouth, and Muscle.