WHY HUMANS AGE

Introduction (2022): I have studied human aging since 1984 when little was known except the free radical theory 1 below, which led to my discovery that 500mg of vitamin C twice a day is required to saturate the blood with this vital antioxidant.  The list of theories with strong evidence is expanding rapidly since 2000, as our population ages.  Some are inter-related but focus on different aspects.  They are numbered below
1. The free radical theory of aging: Developed by Denham Harman, a host of diseases are attributed to free radicals (see Table 1). To lessen free radical damage, one can consume vitamin C 500 mg twice a day, vitamin E 400IU twice a week, and eat a diet of colorful fruits and vegetables that contain a variety of antioxidants.
2. Inflammation (or “Inflammaging” ): Another cause of chronic disease, including plaque in the arteries, cancer, etc. .
3. Telomere shortening.  The length of telomeres, which are caps on the end of the DNA, preserve our genetic information to allow longevity. Actions that shorten telomeres include stress and high metabolic rate.  Consuming antioxidants, staying fit, and relaxing are all useful to keep long telomeres. Note that EGCG and quercetin help maintain telomere length (1).
4. The Translational Infidelity Error Theory of Aging by Dr. Rolf Martin: The basic mechanism is that mRNA is translated incorrectly, incorporating the wrong amino acids into proteins that then fold improperly (based on the AA error theory of  Wolfgang Freist). These proteins are either destroyed, causing a shortage of needed proteins, or worse, remain malfunctioning and accumulating as hazardous waste such as plaque in Alzheimer’s.  Processes that may lessen functional proteins being lost in translation include: 1) increasing the availability of needed amino acids, 2) slowing the rate of translation to increase accuracy, 3) providing time for better proofreading, 4) increasing degradation of misfolded proteins, or 5) diluting the accumulated damage by half through cell division. Helpful actions likely include getting exercise, eating blueberries, drinking green tea, and adjusting the diet to include beneficial foods such as tomatoes, onions, strawberries, and cabbage, which contain less common amino acids.
5. Microbiome destruction – The microbiome is the tremendous numbers of microorganisms that inhabit our intestines, skin, etc.  It contains milllions more genes than our own DNA.  Science now shows that it is responsible for our immune systems, inflammation, weight, and much more. We inherit our microbiomes from our mother’s during natural birth.  Antibiotics destroy it so it must be carefully maintained.
6. Cellular Senescence – Just as telomeres exhaust our cells, other age-related processes cause our cells to lose the ability to divide.  While some senescent cells are beneficial, many produce harmful products and cause inflammation, especially producing arthritis.
7. Thymus failure – As we age, our immune systems grow progressively weaker, with diminished ability to produce B and T cells or respond to antigens sensitively. Vaccines for older adults often have higher doses of antigen.
8. Systemic length-associated transcriptome imbalance – transcript length alone explains most transcriptional changes observed with aging in humans. Three lines of evidence support the biological importance of the uncovered transcriptome imbalance.
9. Deficiency in various vital molecules – There are many molecules that diminish in concentration in areas of the body where they are required, especially in mitochondria, “the power house of the cells” where ATP is generated. As we age, science is discovering many processes and substances that diminish with time.  For instance, much lower niacin levels in mitochondria with age lower the ability to make NAD+ that is essential for energy production, making us more fatigued when older.
10. added July, 2024 – There is good evidence in mice that a molecule called IL-11 is responsible for many processes that cause aging.  Inhibiting IL-11 slows many processes that harm the brain, kidneys, and much more.

11. Added Dec, 2024 – From a long discussion at GRG:

Two things happen in embryogenesis: Yamanaka factors renew the epigenetics and the mother’s mitochondria are winnowed down to a few of the most healthy ones, and these produce all of the mitochondria of the infant.   In principle epigenetic reprogramming can emulate the first effect and massive mitochondrial transplantation can emulate the second. Therefore, through the developing techniques of firms like Turn Bio and Mitrix we are close to the same kind of a rewind that occurs in embryogenesis.

241223 GRG- Thinking that aging is mostly just a result of the four causes you list is wrong and presents a highly oversimplified view of aging. There are many more you are missing, although I will agree that certainly some of them are not as important as the four you mentioned. An important one that I like to draw attention to because I think it’s not getting enough credit is stochastic damages to the extracellular matrix (ECM). Such damages are upstream to many if not most other causes of aging (at the same time they are partially downstream to many of course). As an example, old and damaged ECM is one of the causes of senescence and of age-related epigenetic changes in cells.

241222 GRG You are looking at relatively small effects and mistaking them for the root causes of aging.  I previously posted my list of the important bio-phenomena that are producing the large but treatable aging effects.  They are mitochondrial failure, epigenetic changes, senescent cell buildup, and telomere shortening.  All the other “causes” are likely consequences of these.

Mitochondrial transplantation, by every objective measure, should be the first on this list. Parabiosis and EV/exosome therapies, by the way, are primarily mitochondrial transplant therapies.

https://notebooklm.google/?gad_source=1

Epigenetic changes are a major driver of aging.  Yamanaka factors: These four transcription factors (OCT4, SOX2, KLF4, and MYC) can convert somatic cells into induced pluripotent stem cells (iPSCs), effectively resetting the epigenetic clock34. Partial reprogramming: Small molecules: Using small molecules to target epigenetic modulators offers a promising avenue for rejuvenation fucanoids, a natural product found in brown algae, can activate sirtuins,

SGLT2 inhibitors: Originally developed as anti-diabetic drugs, SGLT2 inhibitors have emerged as potential “gerotherapeutics,”

How to slow these aging processes

Pages related to aging: 1)Aging index 2) healthspan 3) Roc Ordman