The programmed cell death approach to anti-aging treatment

Modern anti-aging treatment is built on a common knowledge base that I will quickly review. Biochemistry and molecular biology tell us that there are many types of chemical reactions in the human body. We know that it is the genetic information programmed into our cellular DNA that defines which reactions occur. Genetic information, expressed in a regulated way, builds the body’s proteins and enzymes and controls how enzymes carry out biochemical reactions in the cell.

This information, contained in the DNA of our genome, consists of many thousands of long, often repetitive sequences of base pairs that are formed from four basic nucleotides. Mapping the human genome has shown that there are more than 3 billion base pairs in our DNA. It is estimated that they contain about 20,000 genes that code for proteins. All bodily functions are controlled by the expression of the genes in our genome. The mechanisms that control the aging process are believed to be programmed into our DNA, but only a fraction of the biochemical reactions related to the aging process have been examined in detail. Cellular aging is a very complex process and many of its low-level operational details have yet to be discovered.

The anti-aging theory has been consolidated in two lines of thought: the theory of programmed cell death and the theory of cell damage. The theory of programmed death focuses on the root causes of aging. The cell damage theory looks at the visible aspects of aging; that is, the symptoms of aging. Both theories are correct and often overlap. Both theories are developing rapidly as anti-aging research uncovers more details. As work progresses, these theories can take years to complete. This broad characterization also applies to the types of anti-aging treatments currently available.

The programmed death theory of aging suggests that biological aging is a programmed process controlled by many life span regulatory mechanisms. They manifest through genetic expression. Gene expression also controls bodily processes such as our body’s maintenance (hormones, homeostatic signaling, etc.) and repair mechanisms. With increasing age, the efficiency of all these regulations decreases. Researchers in programmed cell death want to understand which regulatory mechanisms are directly related to aging and how to affect or enhance them. Many ideas are being pursued, but a key area of ​​focus is slowing or stopping telomere shortening. This is considered one of the main causes of aging.

With the exception of germ cells that produce eggs and sperm, most dividing human cell types can only divide 50 to 80 times (also called the Hayflick limit or biological death clock). This is a direct consequence of the fact that all cell types have fixed-length telomere chains at the ends of their chromosomes. This is true for all animal (eukaryotic) cells. Telomeres play a vital role in cell division. In very young adults, telomere chains are approximately 8,000 base pairs long. Every time a cell divides, its telomere chain loses between 50 and 100 base pairs. Eventually, this shortening process distorts the shape of the telomere chain and becomes dysfunctional. Then cell division is no longer possible.

Telomerase, the enzyme that builds fixed-length telomere chains, is normally only active in young undifferentiated embryonic cells. Through the process of differentiation, these cells eventually form the specialized cells that all of our organs and tissues are made of. After a cell specializes, telomerase activity stops. Normal adult human tissues have little or no detectable telomerase activity. Why? A chain of telomeres of limited length maintains chromosomal integrity. This preserves the species more than the individual.

During the first months of development, embryonic cells organize into approximately 100 different specialized cell lines. Each cell line (and the organs they make up) has a different Hayflick limit. Some cell lines are more vulnerable to the effects of aging than others. In the heart and parts of the brain, the lost cells are not replaced. With advanced age, these tissues begin to fail. In other tissues, damaged cells die and are replaced by new cells that have shorter telomere chains. Cell division itself only causes about 20 telomere base pairs to be lost. The rest of the telomere shortening is believed to be due to free radical damage.

This limit on cell division is the reason why efficient cell repair cannot continue indefinitely. When we are between 20 and 35 years old, our cells can renew almost perfectly. One study found that by the age of 20, the average length of telomere chains in white blood cells is approximately 7,500 base pairs. In humans, skeletal muscle telomere chain lengths remain roughly constant from the early 1920s to the mid-1970s. By the age of 80, the average length of telomeres is reduced to about 6,000 base pairs. Different studies have different estimates of how telomere length varies with age, but the consensus is that between ages 20 and 80, the length of the telomere chain decreases from 1,000 to 1,500 base pairs. Later, as the length of the telomeres shortens even more, signs of severe aging begin to appear.

There are genetic variations in human telomerase. Long-lived Ashkenazi Jews are said to have a more active form of telomerase and longer than normal telomere chains. Many other genetic differences – for example, the efficiency of DNA repair, antioxidant enzymes, and rates of free radical production – affect how quickly you age. Statistics suggest that having shorter telomeres increases your chances of dying. People whose telomeres are 10% shorter than average and people whose telomeres are 10% longer than average die at different rates. Those with the shortest telomeres die at a rate 1.4 times higher than those with the longest telomeres.

Many advances in telomerase-based anti-aging treatments have been documented. I only have space to mention a few of them.

– Telomerase has been used successfully to extend the life of certain mice by up to 24%.

– In humans, telomerase gene therapy has been used to treat myocardial infarction and several other conditions.

– Telomerase-related treatment, mTERT, has successfully rejuvenated many different cell lines.

In one particularly important example, researchers using synthetic telomerase, which encodes a protein that extends telomeres, have extended the telomere chain lengths of cultured human skin and muscle cells by up to 1000 base pairs. This is a 10% + extension of the length of the telomere chain. The treated cells then showed signs of being much younger than the untreated cells. After the treatments, these cells behaved normally, losing a part of their telomere chain after each division.

The implications of successfully applying these techniques in humans are staggering. If telomere length is a major cause of normal aging, then using the telomere length numbers mentioned above it might be possible to double the healthy period of time during which telomere chain lengths are constant; that is, from the range of 23 to 74 years to an extended range of 23 to 120 or more years. Of course, this is overly optimistic because it is known that cells grown in vitro can divide a greater number of times than cells in the human body, but it is reasonable to expect some improvement (not 50 years, but 25 years).

We know that telomerase-based treatments are not the final answer to anti-aging, but there is no doubt that they can, by increasing the Hayflick limit, extend or even immortalize the lifespan of many types of cells. It remains to be seen if this can be done safely in humans.