The hallmarks of aging as elaborated in the now famous paper are the key biological changes that occur in living organisms as they grow older. These changes are thought to be the underlying cause of many of the health problems associated with aging, such as loss of muscle mass, declining cognitive function, and increased susceptibility to disease. The nine hallmarks of aging are:
- Genetic instability – accumulation of mutations in the DNA
- Telomere attrition – shortening of the protective caps on the ends of chromosomes
- Epigenetic alterations – changes in gene expression that do not involve changes to the underlying DNA sequence
- Loss of proteostasis – decline in the cell’s ability to maintain the proper folding and function of proteins
- Deregulated nutrient sensing – changes in the way cells respond to nutrients and growth signals
- Mitochondrial dysfunction – decline in the function of the mitochondria, the cell’s powerhouses
- Cellular senescence – accumulation of cells that can no longer divide and perform their functions
- Stem cell exhaustion – loss of stem cells and their regenerative abilities
- Altered intercellular communication – changes in the way cells communicate with each other.
These changes are thought to contribute to the aging process and the development of age-related diseases.
Of course, these hallmarks have raised the very important question of whether there is one process to rule them all. Do all of these hallmarks accumulate with the passage of time or are they programmed in some way. That is the question and at this time there are only theories.
Attempts at “treating” or forestalling aging, focus on these hallmarks.
1. MTOR inhibition.
MTOR (or mechanistic target of rapamycin) is a highly conserved kinase (or enzyme) present in all cells in almost all forms of life. It’s purpose is to sense whether or not the organism is in a fed state, and if so, it signals cell growth and expansion in numerous ways. Conversely, if the enzyme senses a lack of nutrition, it puts the cell in a state of frozen animation that theoretically permits it to persist until the time that nutrition is readily available. Supporting this theory of aging, calorie restriction with adequate nutrition has been shown to extend lifespan in a wide range of life forms: yeast, worms, flies, mice and monkeys. But not yet humans, because it’s very hard to do lifetime experiments to test this in people. Even so, there is plenty of evidence that reducing calories decreases metabolism, reduces oxidative damage to tissues and profoundly changes the body in lasting ways. The challenge is to derive these benefits without resorting to severe caloric restriction, which is widely considered not fun.
2. Cellular senescence
Cells can enter a zombie state called senescence in which they no longer grow or divide but they take up space and even secrete inflammatory factors into the local environment that persuade other cells to become senescent. They can be detected histologically by stains that turn the senescent cells blue, which allows us to see the profound burden of senescence in older individuals. Senescence may have some utility to the organism in facilitating scarring and perhaps other necessary roles, but removing senescent cells has been shown to have remarkable rejuvenating effects in older lab animals. A number of companies are banking on the theory that we will oneday treat disease or rejuvenate older individuals with senolytic medications.
3. Mitochondrial aging
Mitochondria are the engines of the cell that provide us with energy. They are likely foreign bacteria that were captured into a symbiotic relationship early in evolution, that have been incorporated into our cells and are not virtually indistinguishable from their hosts (other than having separate DNA). As we age, they age as well and we perceive this decline in number and function as a diminishment of energy. Are there ways to rejuvenate mitochondria? The answer is probably. Certainly exercise, and in particular zone 2 exercise, has been shown to improve mitochondrial function. Beyond that there are supplements that have been shown to support mitochondrial function, especially in old age, with resulting improvements in cognition and muscle strength.
4. Epigenetic changes / Reprogramming
We are born with certain genes that do not change, but which genes are used or expressed changes over time and in response to the conditions of life. Epigenetics refers to changes of gene expression that happen without changes to the DNA coding sequence. These changes are put into action by changes in DNA methylation and acetylation patterns, modification of histone, and chromatin remodeling.
Methylation (or acetylation) of DNA by repair enzymes changes the proper analog folding and orientation of DNA chromatin strands in the nucleus leading to epigenetic phenotypic changes. We age because our cells forget the original intentionality that is encoded in the epigenome. Basically, youth → living → broken DNA → genome instability → disruption of DNA packing and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death. Steven Horvath and others have analyzed these methylation patterns and their predictable progression and claim to be able to use them as a biomarker for aging. You can pay to get your biological age typed with a Horvath clock. Or a Grim clock or other clocks. The undoing of this methylation could theoretically reprogram cells and rejuvenate organisms and there is some experimental evidence that it works, but this is seemingly far from widespread application or availability. Some lower life forms (sponge, hydra) have access to the germline that can reset methylation to an earlier state. According to this theory, they should be immortal. And it turns out that they are. Sinclair and others believe that germline information can be reintroduced into somatic cells by way of adenovirus vectors to restore youthful phenotype.
**In less than a year, this technology seems closer to fruition.