Abstract
Attaining immortality or finding the fountain of eternal youth have been recurring themes and a constant quest of mankind since time immemorial. According to the book of Genesis, Methuselah must have been pretty close because it states that he lived to be 969 years old; hence the saying “older than Methuselah.”
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Notes
- 1.
The first 1–4 years of life are the most critical in human survival. During these years we are still developing our immune system, so we are more vulnerable to all kinds of infections. After this threshold, especially in the first year of life, the chances of survival increase drastically. The main pathologies responsible for these child deaths worldwide include malaria, pneumonia, diarrhea, premature births and other neonatal infections. To give an idea of the importance that infant deaths have had on average life expectancy throughout history, it is considered that the control of infant mortality alone is responsible for 50% of the increase in longevity achieved.
- 2.
According to the European Statistical Office (Eurostat), the main causes of death in the European Union are circulatory diseases, followed by cancer, COVID-19 and respiratory diseases. Likewise, the National Center for Health Statistics (NCHS) reports heart disease, cancer, and COVID-19 as the leading causes of death in the USA. On the other hand, if we look at developing countries where basic public health measures have yet to be implemented, the main causes of death are mostly due to respiratory infections, diarrhea, malaria or, complications related to childbirth.
- 3.
For a cell to divide, it must first duplicate the genetic information contained in its chromosomes. This is the only way for each of the two resulting daughter cells to contain a complete copy of its DNA. This process, called replication, is carried out by the enzyme DNA polymerase, the function of which is to attach itself to the DNA, read its nucleotide sequence (the letters that compose it), and select the pieces to synthesize an identical copy. This enzyme is only able to copy the sequence in one direction. For one of the two strands of DNA this is no problem: the DNA polymerase copies its sequence from start to finish. For the other strand, which runs in the opposite direction, a little help is needed in the form of blocks of RNA. These blocks, known as primers, mark the start of synthesis for a new piece of DNA known as the Okazaki fragment. Subsequently, the primers will be replaced by DNA and the Okazaki fragments linked together. These fragments will be formed consecutively Along the chromosome, but at the end of the DNA, at the telomere, this will not be possible: there is no space to place a primer to mark a new beginning. As a consequence, the telomere becomes shorter and shorter with each replication. The wear and tear and loss of the telomere prevents it from performing its protective function for the chromosome, making it unstable and more vulnerable. Cells with critically short telomeres are unable to divide, cease to be viable, and activate cell death mechanisms.
- 4.
The insulin-PI3K signaling pathway is one of the main pathways involved in aging. In fact, partial inhibition of its activity protects against cancer, improves insulin sensitivity, and increases longevity in a wide variety of organisms. Their activation occurs when insulin, IGF1 or GH bind to their corresponding receptors located in the cell membrane. Once this extremely specific binding occurs, the phosphokinase PI3K is recruited to the cell membrane and activated. As a consequence, PI3K performs its function as a phosphokinase by phosphorylating (adding a phosphate group) the phospholipid PI(4,5)P2 to generate PI(3,4,5)P3. PI(3,4,5)P3 in turn acts as a secondary messenger that transmits the activation signal to a group of proteins containing a PH (pleckstrin homology) domain including AKT, mTORC2 and PDK1. It is these latter members that promote growth, survival, or division responses in cells.
- 5.
Amino acids are the organic units that make up all proteins. There are 20 different amino acids, of which 9 are called "essential.” Unlike the nonessential ones, the essential amino acids are those that, being essential, the body itself is not able to synthesize, so they must be ingested with the diet. In this group we find, among others, tryptophan and methionine.
- 6.
Ketogenic diets are those diets characterized by a high content of fat and protein, and a low percentage of carbohydrates (glucose), and usually prescribed mainly as a treatment for childhood epilepsy. Its name alludes to its ability to generate a response similar to fasting known as ketosis, in which, in the absence of glucose, the body is forced to burn fat. In these circumstances, fats are converted into fatty acids and ketone bodies that will become the main source of energy for the brain, replacing glucose.
- 7.
Rapacimin is the calorie restriction mimetic that has thus far proven to be the most efficient in mice trials. Another compound of great interest to scientists is metformin. This is a drug commonly used for the treatment of type 2 diabetes that increases insulin sensitivity. Although it does not extend life expectancy in many of the organisms in which it has been tested, metformin continues to receive a great deal of attention because it has a very similar effect to calorie restriction on gene expression. Resveratrol, a compound found in red grapes and wine, entered the calorie restriction mimetic scene with a vengeance. At first it seemed that its use was indeed able to delay aging in several laboratory organisms, and reduce the risk of several age-related pathologies. However, little by little it has been seen that the effects of resveratrol are not as wonderful as expected, and currently we have inconsistent publications and very little evidence to support its real benefits on aging, cardiovascular diseases or cancer.
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López Guadamillas, E. (2024). The Science of Living Longer. In: M. Garcia, M. (eds) Tales of Discovery. Springer, Cham. https://doi.org/10.1007/978-3-031-47620-4_6
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