As a species, we humans are not specifically designed to age and expire. However, the processes in our body are biologically imperfect which results in unintended consequences as part of normal bodily functions. Furthermore, some of our cells and structures are irreplaceable by design (neurons, skeleton, heart, eye lens, teeth, etc). As time goes by, damages to our various systems progressively accumulate and synergize. We can cope with most of the damages for a while, but eventually, our repair and defense mechanisms get overwhelmed. This is when we start noticing changes and eventually we are taken down by various system failures – diseases of old age (arthritis, cancer, heart disease, diabetes, hypertension, dementia, osteoporosis, etc).
The scientific community interested in life extension has identified the root causes of aging as follows:
These are collectively known as the hallmarks of aging. Let’s briefly examine them:
Genomic Instability (DNA damage)
DNA is the biological blueprint for everything our cells need to produce so that our body can develop and function normally. Every cell (with some exceptions) holds the complete copy of our DNA. The DNA is constantly bombarded by external factors such as UV rays, radiation, chemicals, but also internal factors such as reactive oxygen and nitrogen species – free radicals, which are an undesired consequence of the normal cellular functions (energy production, etc). On a daily basis, the DNA in most cells gets broken and deformed thousands of times. Luckily we have an elaborate arsenal of repair systems which successfully take care of 99.9% of these damages. These repairs, however, are not perfect, so the leftover damage accumulates with time. An unrepaired defect is not a big deal unless it happens at a critical place in the DNA (broken gene) or to a critical cell (stem cell). Such damages may then lead to cancer, loss of function, production of broken proteins which may inflict further damage to the body, cellular senescence or if we are lucky cell death (apoptosis). With time the accumulation of such damages eventually leads to critical system failures (disease, death).
Further learning material and references:
Telomere attrition (replicative aging)
Telomeres are the protective caps at each end of our chromosomes – much like the plastic tips at the end of shoelaces. They are comprised of a specific DNA sequence (TTAGGG) which is repeated thousands of times. Each time a cell divides, the telomeres get shorter. Eventually, after 50-80 divisions (Hayflick limit) they get so short, that the DNA is not protected anymore. This would lead to various problems like DNA damage, the ends of chromosomes fusing with other molecules, etc. To prevent that from happening, the cells which run out of telomeres either die or retire – transform into senescent state and stop dividing. The growth and renewal potential of our somatic cells is thus also limited by shortening telomeres. Some types of cells have a solution to this problem. Stem cells, the germline and T lymphocytes to name a few, produce a protein complex called telomerase, which keeps adding telomeres to the ends of their chromosomes. The cells with sufficiently active telomerase have an unlimited dividing potential. Unfortunately, cancer cells also fall into this category. Active telomerase does not cause cancer but it is a necessary component for the cancer cells to keep multiplying.
Telomeres are influenced by many factors including oxidative stress, chronic inflammation, body mass index, smoking, alcohol intake, and perceived stress. Interestingly habitual physical exercise has shown to increase the length of telomeres. Other than protecting the DNA from one type of damage and extending the ability for the cells to replicate, active telomerase also lowers the incidence of inflammatory diseases, glucose intolerance and improves neuromuscular coordination (at least in mice).
It is understood that telomere shortening may contribute to aging by preventing unlimited renewal of cells, however many cells in the human body do not replicate, so telomere shortening is not an issue with those.
Further learning material and references:
Epigenetic alterations (epigenetic drift)
Except for an occasional mutation, the DNA is a fixed, static blueprint for all our biological processes. Since each of our cells has the exact same copy of it, why do the cells look and function so differently – why don’t teeth grow out of our eyes? The epigenome is a layer of chemical compounds covering the DNA and hovering all around it. It controls which parts of the blueprint can or cannot be read and thus translated into action. This defines the identity of a cell. It’s like a dimmer switch for genes. If DNA is analogous to computer hardware, the epigenome can be seen as software. We could also imagine the DNA as a railway track, where the epigenome would be analogous to grass and rocks covering some parts of the track – preventing the trains to go there. On the other spectrum, the railway also leads to popular cities like Las Vegas, which means surrounding parts of the track are used more often.
Unlike the static DNA, the epigenome is highly flexible and adapts to the environment and experiences rapidly. This is the reason why your lifestyle (diet, fitness, stress, etc) affects your body composition, health, and longevity.
Imagine a room full of dominoes of different colors and shapes, all arranged to follow a pattern of falling (example: https://www.youtube.com/watch?v=lo6x4eulY9g). This is similar to how the epigenome is set to control the progress of our development since conception. Every step causes a chemical chain reaction which triggers the next stage of development throughout our lives. As we develop and grow, our cells multiply and irreversibly specialize into organs. This is achieved by a unique epigenetic landscape for different groups of cells.
Unfortunately, things change for the worse with age. Epigenetic drift is the progressive accumulation of changes in the epigenome. This is analogous to your cells slowly falling asleep at the wheel and gradually sliding off the highway towards the forest. The deregulation of epigenetic patterns are tissue-specific but they happen all over the body. Epigenetic clocks have been developed (Steve Horvath), which measure these changes and can determine the biological age of the organism within +/-3 years precision.
Fortunately, several groups of scientists have been working on correcting the epigenetic drift. This is currently, experimentally done by reverting the epigenetic changes but stopping before the cellular identity is erased. Exposing the cell to the Yamanaka factors (Oct4, Sox2, Klf4, and optionally c-Myc, also known as OSKM / OSK) gradually reverts the epigenome. Under continuous exposure, the process reverts the cell all the way back to the original pluripotent stem cell. We seem to be onto something good here, but the process needs to be perfected and well understood before it is made into a viable anti-aging therapy. Some scientists have high hopes, that solving the epigenetic aspect would simultaneously solve most other hallmarks of aging.
C-Myc is an oncogene which has a high potential to induce cancer. In 2016 Yuancheng Lu from David Sinclair’s lab discovered that the epigenome can be reset even by excluding the c-Myc factor. Since then Sinclair’s lab has devised a successful method of reverting the epigenome to a younger state. This is done with gene therapy introduced and transiently activated OSK factors. The research paper is available here.
Further learning material and references:
Loss of proteostasis
Proteins are complex molecules essential for the structure, function, and regulation of the body’s cells, tissues, and organs. The proteome is the entire range of proteins which can be produced by a cell, tissue or the organism. A cell can express over 10.000 unique proteins at any given time, which then have to undergo precise folding and assembly to well defined 3D structures. Only as such, they can serve a specific purpose. Due to various stressful conditions, proteins can deform, unfold or aggregate – as such become dangerous to the body. After they have served their purpose and are no longer required, proteins must be destroyed to avoid unwanted effects of their continuous presence.
Proteostasis is a state of equilibrium when all the proteins are balanced and functioning correctly. Proteostasis network is a group of specialized factors which coordinate protein synthesis, folding, maintenance, quality control and recycling. It senses and responds to proteotoxic stress and protein misfolding to protect the cells. Because of its vast complexity, the protein folding process is prone to errors. A properly functioning proteostasis network is thus essential for prevention off protein-caused diseases of old age, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS).
Proteins are the
Deregulated nutrient sensing
Stem cell exhaustion
Altered intercellular communication
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- Lu, Y. et al. Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming. bioRxiv 710210 (2019). doi:10.1101/710210
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- Gladyshev, V. N. The free radical theory of aging is dead. Long live the damage theory! Antioxid. Redox Signal. 20, 727–31 (2014).
- López-Otín, C., Galluzzi, L., Freije, J. M. P., Madeo, F. & Kroemer, G. Metabolic Control of Longevity. Cell (2016). doi:10.1016/j.cell.2016.07.031