Our genome consists of more than 3 billion nucleotides of four types: adenine (A), cytosine (C), guanine (G), and thymine (T). The individual DNA strands are wrapped around proteins called histones in the cell nucleus. Both DNA and histones can contain small chemical changes that can be used to switch individual genes on or off. The compound of these chemical changes is called the epigenome. The epigenome changes as we get older. Some of the chemical changes are misplaced, added in the wrong place, or lost. As a result, the control over gene activity also changes. Our epigenome is influenced by our diet and lifestyle, but chronic stress or certain drugs can also change it.
4. Loss of proteostasis
The DNA of our cells contains the instructions for all cellular functions. However, DNA does not carry out these functions. Instead, our DNA contains the information for the production of proteins and enzymes that take over tasks and control processes within the cell. Proteins and enzymes control all chemical reactions in the cells and also give the cell its structure.  To carry out such functions, proteins must be folded precisely into a very specific structure, similar to origami. The term protein homeostasis, or proteostasis for short, describes the maintenance of the form and abundance of all proteins.
As we age, proteins get increasingly damaged due to normal cellular processes, which also influence their shape and folding. Not only can misfolded proteins no longer perform their normal work, but they also tend to clump together, which can have a toxic effect on the cell. For example, Alzheimer's disease is an age-related disease caused by misfolded proteins. Because the maintenance of proteostasis is so important the cell has several mechanisms to control the folding and quality of proteins. Our cells not only have mechanisms to repair and refuel distribute proteins there are also mechanisms to degrade such proteins and replace them with new ones. Misfolded and damaged proteins, for example, can be degraded by a recycling process known as autophagy.
Many study results suggest an important role of proteostasis in aging: misfolded proteins increase with age; several age-related diseases such as Alzheimer's are associated with misfolded proteins; improving protein quality control increases the lifespan of mice and other model organisms. 
5. Deregulated nutrient-sensing
When sufficient nutrients are available, cells and tissues store energy and grow, whereas when nutrients are deficient, mechanisms for homeostasis and repair are activated. When cells are constantly exposed to excess nutrients the cellular mechanisms that recognize nutrients become less sensitive. This process also occurs during aging and causes cells to fail to respond properly to the signals that normally regulate energy production, cell growth, and other important cellular functions. Many studies have investigated the effect of food intake or the perception of food on the aging process- for example, when the overall food intake is reduced when the body is tricked to believe it has less food the insulin signaling pathway is switched off, and the lifespan increases in fruit flies. The result of many studies is that reduced food intake improves health and increases the lifespan of a wide range of animals.
Two nutrient-sensing pathways are especially the focus of aging research: The insulin/insulin growth factor (IGF) and the Target of Rapamycin (TOR) pathway together constitute a key nutrient-sensing network within the cell.  Genetical or pharmacological inhibition of the insulin/TOR network extends the lifespan in a wide range of animals, making it a prime target for the development of anti-aging drugs.
6. Mitochondrial dysfunction
This cell needs the energy to sustain all its cellular functions and chemical activities. This energy production takes place in the mitochondria, by utilizing the oxygen we breathe in. however this process sometimes produces free radicals so-called reactive oxygen species, or ROS for short.

ROS can damage just about every molecule in the cell. For a long time, it was thought that ROS were the main drivers behind the aging process. However, it has been known for some years now that reducing ROC Level sometimes does not affect health at all. Cells, organs, and tissues that perceive stress increase their maintenance and repair processes in response to it. For healthy aging, the amount of ROS must therefore be just right: not too much and not too little.
In general, critical cellular signaling pathways are functions that can be impacted by mitochondrial dysfunction. Over time the cell’s ability to produce energy decreases and at the same time the level of oxidative stress rises, damaging other cellular elements. Therefore, mitochondrial dysfunction plays a role in several age-related illnesses including myopathies and neuropathies.
 
7. Cellular senescence
Cell division helps an organism grow or allows further replacement of aged cells in specific tissue or organ. However, this ability eventually wears out since most of the cells are unable to divide permanently. senescent cells are those that have stopped reproducing permanently. However, these cells do not die instead a few of them discharge harmful chemicals into their surroundings which can harm neighboring cells. Telomere shortening Is one of the factors in cellular senescence. However, there are a few other factors, such as DNA damage, that can cause a cell to enter a senescent state.
For a long time, it was unclear whether senescent cells contribute to the aging process or are effective protection against the development of cancer.  A recent study has shown that senescent cells decreased survival even in young mice. Drugs that kill or silence senescent cells are called senolytics and are now being tested for their potential beneficial effect on humans regarding aging.
 
 
 
8. Stem cell exhaustion
It is essential for the health of our body that tissues and organs can renew old cells and repair damage. The ability of our body to renew parts of tissues and organs is based on stem cells, which are present in almost every tissue. Since stem cells can theoretically divide indefinitely and thus create new cells, they are the ultimate source of new cells.
Healthy stem cells must be able to divide when the body or specific tissue needs new cells. The ability of stem cells to divide the ability to divide only when new cells are needed decreases with age. In the worst case, the unstopped division of cells can lead to cancer.
Many studies have shown that certain molecules, for example, the drug rapamycin, can maintain the functions of stem cells and thus not only improve the health of stem cells but also have a positive effect on the body's aging process.
9. Altered intercellular communication
The cells in our body communicate with each other this communication is essential for our health and also influences our aging process.  Cells can use many forms of communication. if they want to communicate with the neighboring cell they communicate via their physical connection by releasing certain molecules. However, it is also possible to reach cells that are not in the immediate vicinity. By secreting hormones into the bloodstream, it is even possible to reach recipients located in completely different regions of the body and different organs can communicate with each other in this way.  This impaired communication leads to problems such as chronic tissue inflammation as well as the failure of the immune system to recognize and eliminate pathogens or defective cells, increasing susceptibility to infections and cancer.
 
 
These nine hallmarks are a good way to describe the mechanism of how we age, but why did evolution make us age?
one popular aging theory was proposed by evolutionary biologist Peter Medawar. The “mutation accumulation” theory states that the force of natural selection stays high until first reproduction, afterwards it declines with age. Hence harmful mutations whose effects only occur later in life can accumulate because they are not selected against.

 After reproduction, there is no evolutionary pressure to ensure the continued survival of the organism. Cellular processes decline, the organism ages and ultimately dies.
The “antagonistic pleiotropy” theory by George Williams states that natural selection can favor gene variants with beneficial effects early in life, even if the same variants have detrimental effects later. Natural selection cannot directly select against a gene or its mutation if its harmful effects do not occur before the end of the reproductive phase.
 
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*November 21, 2022*
*Glutaminase inhibitors rejuvenate human skin via clearance of senescent cells: a study using a mouse/human chimeric model*
https://www.aging-us.com/article/204391/text

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