Aging clocks and measuring biomarkers of age

Epigenetic predictors of mortality and susceptibility to disease

Have you ever wondered how old are you really, not chronologically but biologically? It may appear intuitive as some people don’t look their age but we now have applicable methods to help identify a person’s real age. Among the first and the better-understood methods of measurement is a Horvath epigenetic clock. It is a remarkably stable and reliable method of identifying a person’s biological age, which may not necessarily match the chronological age. 

The key hallmarks of aging are more accurate predictors of the relative age of individuals and they include the following:

• Genomic instability
• Epigenetic alterations
• Loss of proteostasis
• Dysregulated nutrient sensing
• Mitochondrial dysfunction
• Cellular senescence
• Stem cell exhaustion
• Altered intercellular communication

Differences between chronological and biological age

Chronological age:

“A legally accepted measure of age that has passed since birth. Zero is the time at birth. Prenatal (before birth) months are in negative numbers i.e. -3 months and postnatal ages are identified in positive numbers i.e 35 years, 4 months, and 2 days”

Biological age 

“Also known as physiological age, organismal age, and phenotypic age. This could mean an array of things but primarily it is dependent on the physical health of an individual “.

So how do we measure the difference between individuals?

Hallmarks of aging are not the same things as the causes of aging, however, they are very much entangled. In science, the word cause is rarely used because it implies a direct effect, which is often untrue. It is unscientific to claim that aging is directly caused by something distinct, so we use words like evidence and hallmarks to present findings of correlations and logical implications. These correlations and implications may lead to a more complete understanding of a particular subject such as aging. So here we have the hallmarks of aging, also known as biomarkers, they are the signs and indications of the speed of aging that can predict whereupon the lifeline you are with frightening accuracy. 

The Horvath clock

The Horvath clock is an epigenetic clock that can estimate tissue age by comparison to other tissues. This epigenetic clock uses the DNA methylation profile of cells to identify the stage of life of nucleated cells. Methylation-based age estimators turn out to be very reliable. 

Instead of using time, to state chronological age, scientists can now measure profiles of biological molecules (methyl groups) that are attached directly to cytosines on the DNA (cytosine is a pyrimidine base, C4H5N3O, which is one of the fundamental components of DNA and RNA, in which it forms a base pair with guanine.) on the DNA [1]

The scientific field of epigenetic aging is a recently discovered branch of DNA research and our insight into aging is growing rapidly. Discoveries and, more importantly, practical implications of research give hope to finding a solution to aging eventually. Perhaps one day we could eliminate aging altogether. 

Epigenetic aging addresses many pathologies, health conditions, lifestyle choices, and external stressors that are associated with changes to the rate of epigenetic aging. This means that we can already pinpoint where we’re going wrong in our life. However, despite being strong indicators of the effect of aging, we remain largely in the dark as to the underlying mechanisms of aging.

While these associations highlight and affirm the ability of the epigenetic clock to capture biologically meaningful changes associated with age, they do not inform us about the underlying mechanisms. So there is still work to be done on that front. However, epigenetic clock theory holds based on these points:

• These markings exist in seniors and even in fetuses and it is close to zero in embryonic and induced pluripotent stem cells  [2]
• These epigenetic markings correlate with cell passage number 
• It gives rise to a highly heritable measure of age acceleration
• It applies to other species such as chimpanzees

The differences between biological age and chronological age illustrate which interventions and which lifestyles are better for health.

Other hallmarks of aging correlate with biological age.

The Horvath clock can be used to predict the like liability of the onset of age-related illnesses, and the health span. Since the information is genetic, it is truly innate to the organism.

Children often inherit their parents’ longevity, and their epigenetic clock ticks slower.

When does the aging clock start ticking?

Epigenetic clocks start ticking before you’re born, on day 8 of gestation according to Vadim Gladyshev, a renowned scientist in the field of aging.

Biomarkers of aging (hallmarks of aging)

Identifying hallmarks and biomarkers of aging is the first step in the scientific fight against aging. It allows us to understand how aging happens on a genetic, molecular, and cellular level to distinguish signs of accelerating and decelerating aging. Hallmarks and biomarkers are measurable and distinguishable signs.

According to the American Federation for Aging Research (2016), a true biomarker of aging should meet the following criteria [3]:

• 1) predict remaining life expectancy better than chronological age,
• 2) monitor mechanisms underlying the aging process but not a specific disease,
• 3) be subject to repeated tests without harming the individual,
• 4) be testable in both laboratory animals and humans.

Another way to look at each ‘hallmark’ is that it should ideally fulfill the following criteria: (i) it should manifest during normal aging; (ii) it’s experimental aggravation should accelerate aging; and (iii) its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan [1].

Since aging is an extremely complex multivariate process involving multiple molecular pathways operating at many levels of the functional organization, it is unlikely to be evaluated with a single biomarker. That’s why we have hallmarks.

Major challenges with biomarkers of aging

All of the biomarkers are interlinked. A major challenge is figuring out what is causal and what is correlative in terms of these biomarkers. Another challenge is to establish their relative contributions to the speed of aging and how they interact with one another [1].

Another massive problem is that most of the tests required to measure these hallmarks are very technical which means the testing is expensive. Some of the hallmarks can only be measured with a niche, specific machines, and understood by trained specialists, which limits the testing accessibility to the public.

Will we be able to stop aging altogether?

If you can measure something you can see if it stops changing. Measuring biomarkers would eventually pave the path to measuring the success of anti-aging treatments and interventions.

Eventually, we may be able to find an intervention to stop aging or reverse it. Because aging is something that happens over a long time, there are a lot of obstacles. To find the cause of aging we need to identify what slows down aging and what accelerates it. Pinpointing these biomarkers of aging will allow us to compare interventions by efficacy. In terms of science and research, these hallmarks of aging are an insight into the physical state of our bodies.

The aging process is complicated but there are a few things we know about aging on the cellular/molecular level. Before we notice the changes physically in our bodies such as declining physical health and cognitive abilities we can see what changes are happening on a microscopic level in our cells and the DNA inside of those cells.

Science is moving very fast and specialized professionals are working to create more accurate and more affordable machines that will make testing hallmarks of aging accessible to more individuals.

DNA sequencing progress and costs vs anti-aging tech

The sequencing of the first human DNA cost 2.7 billion and it took 15 years, completed in 2003. Today DNA can be sequenced and analyzed for under 1000 dollars and over the weekend. The technical progress along with more funding being put towards developing better and more affordable means of measuring aging is a cause for optimism. DNA analysis is one of the more promising methods of researching health.

Preventing aging could be just a problem that needs proper funding for creating technology and finding people to drive it forward. The science of health, especially slowing down aging is immensely complicated but some of the world’s best minds are working towards slowing down aging and reversing it.

There is a lot of optimism in the anti-aging field today, but to see what works and what does not, measuring the hallmarks of aging is essential.

Major Hallmarks of Aging

There are at least 9 major biomarkers of aging on a cellular/DNA level. Some are

There are several major hallmarks of aging, which refer to the underlying biological processes that contribute to the decline in physiological function and the increased risk of age-related diseases that occur as we get older. These hallmarks of aging include:

1. Genomic instability: Refers to damage to our DNA, which can lead to mutations, cell death, and an increased risk of cancer.
2. Telomere attrition: Telomeres are the protective caps on the ends of our chromosomes that shorten each time a cell divides. Over time, this can lead to cellular senescence (a state of permanent cell cycle arrest) and age-related diseases.
3. Epigenetic alterations: Refers to changes in the way genes are expressed that occur over time and can affect how cells function.
4. Loss of proteostasis: Refers to the decline in the body’s ability to maintain protein function and quality control, which can lead to the accumulation of damaged or misfolded proteins.
5. Dysregulated nutrient sensing: Refers to changes in the body’s ability to respond to nutrient availability, which can contribute to metabolic dysfunction and age-related diseases.
6. Mitochondrial dysfunction: Refers to the decline in the function of the mitochondria (the powerhouses of the cell), which can lead to decreased energy production and increased oxidative stress.
7. Cellular senescence: Refers to the accumulation of cells that have stopped dividing and are no longer able to contribute to tissue regeneration.
8. Stem cell exhaustion: Stem cell exhaustion refers to a decline in stem cell numbers and renewal capacity function. With age tissues and organs suffer damage and without Without stable populations of proliferating stem cells, tissues, and organs lose their ability to recover from damage and begin to fail.
9. Altered intercellular communication: Cells communicate to deliver messages and pinpoint problems. Intercellular communication also allows for the control of metabolic processes throughout the body. When this function is hindered, metabolic processes suffer as a result.

These hallmarks of aging are measured in various ways, depending on the hallmark and the research context. For example, genomic instability can be measured by assessing the frequency of DNA mutations or chromosomal abnormalities, while telomere attrition can be measured by examining telomere length. Epigenetic alterations can be measured by assessing changes in DNA methylation patterns, while mitochondrial dysfunction can be measured by examining markers of oxidative stress or mitochondrial function.

Measuring the state of these biomarkers of health allows us to measure how well we are doing in terms of aging. Aging clocks are a combination of these measurements.

1. Genomic instability

Telomere attrition

Epigenetic alterations and DNA methylation

Loss of proteostasis

Dysregulated nutrient sensing

Mitochondrial dysfunction

Cellular senescence

Stem cell exhaustation

Altered intercellular communication