1. Genomic Instability 

DNA is the blueprint for your cells, providing the instructions for how they function. However, DNA faces constant damage from various sources such as UV radiation, cigarette smoke, alcohol, free radicals produced by normal metabolism and even from the process of DNA replication itself.

 

To combat this, cells have very robust DNA repair mechanisms, however these become less effective with age, leading to an accumulation of DNA damage which stops cells from functioning correctly.

 

2. Telomere Attrition

Telomeres are the caps at the end of your DNA that protect it from damage during cell division. They are often depicted as the caps at the end of shoelaces.

 

Every time a cell divides the telomeres become shorter and eventually disappear completely. This signals that the cell is 'old' and should not undergo further replication.

 

3. Epigenetic Alterations 

Epigenetics are the biochemical markers attached to DNA that control which genes are switched on and off, giving cells their specialised functions.

 

Studies show that the expression pattern of epigenetic markers changes with age causing cellular dysfunction. Genes which shouldn’t be switched on become active, as changes in epigenetic markers mean that the cell accesses large portions of DNA it shouldn’t. This causes cells to lose their specialty and their identity. They no longer perform their functions due to this ‘cellular confusion’.

 

4. Loss of Proteostasis 

The human genome encodes around 80,000 different proteins, that are critical to cellular function. Proteins are 3D structures and their shape (which is based on how they are folded) determines their function. If they are folded incorrectly, vital cellular processes will not function. Proteostasis is the quality control system that ensures all proteins in the cell are folded and functioning correctly.

 

As we age this system becomes dysfunctional, it cannot detect damaged proteins and cannot repair them effectively, leading to protein aggregation - large lumps of protein stuck together which causes damage to the cell.

 

5. Deregulated Nutrient Sensing 

During aging the pathways which determine how our cells detect and respond to nutrients become dysregulated. The main nutrient sensing pathways are:

• IGF-1– activated by insulin when levels of glucose in the bloodstream increase
• mTOR– activated by high amino acid (protein) levels
• Sirtuins– activated by NAD+, which is increased when there is low cellular energy
• AMPK– activated by AMP, which is also increased in response to low cellular energy

 

Sirtuins and AMPK are known to decrease in activity with age. As they regulate many of the repair pathways within the cell, this contributes to the accumulation of cellular damage.

Opposingly, mTOR and IGF-1 overactivation accelerates aging and it has been found that inhibition of mTOR and IGF-1 via calorie restriction have a beneficial impact on cellular health.

 

6. Mitochondrial Dysfunction 

Mitochondria are often referred to as the ‘powerhouses of the cell’ as they are responsible for cellular energy (ATP) production. Therefore, ensuring mitochondria are functioning optimally is very important.

 

During aging the quality and quantity of the mitochondria decline, causing decreased energy production, contributing to the feeling of exhaustion associated with aging. This occurs for several reasons:

• Increased mitochondrial damage by free radicals (produced during energy production)
• Decreased mitophagy (the process which maintains the quality of mitochondria)
• Decreased production of new mitochondria

 

7. Cellular Senescence 

Senescence occurs when a cell is prevented from replicating because it has become damaged beyond repair. In this senescent state, cells no longer replicate to prevent the spread of the damaged DNA, but are still metabolically active meaning they can still interact with surrounding cells. This is why they are often referred to as ‘zombie cells’.

 

Certain senescent cells develop a Senescence Associated Secretory Phenotype (SASP). Meaning the cell secretes pro-inflammatory factors into the cellular environment causing neighbouring cells to also become senescent. Senescent cells increase inflammation but also cause increased expression of CD38 which is known to deplete NAD+ levels.

 

8. Stem Cell Exhaustion

Stem cells are the bodies building blocks, creating many different types of specialised cells. The main function of stem cells is to replenish damaged and old cells in response to injury.  Whilst they have self-renewal properties, stem cells are still susceptible to damage themselves.

During aging, stem cells accumulate DNA damage and dysfunctional mitochondria which impairs their ability to self-renew contributing to the decline in the regenerative capacity of organs and tissues.

 

9. Altered Cellular Communication

It is important to remember that cells do not exist in isolation. Cells, tissues and organs are all connected and constantly in communication with each other allowing your body to quickly respond to changes. When this cellular communication is lost it impacts cellular function negatively.

 

One key example of cell communication is inflammation. This is a natural response to injury, signalling that there has been damage which requires fixing. However, with age, inflammation becomes constant and not just when injury has occurred.  This causes damage to tissues and accelerates aging further.

 

10. Loss of Autophagy

Autophagy is the process by which damaged cellular components such as proteins, mitochondria, lysosomes, and other cellular structures are broken down and recycled. Autophagy is critical for optimal cellular function as damaged cellular machinery cannot operate correctly, leading to an accumulation of cellular damage.

Human studies show the expression of genes involved in autophagy decline with age, causing reduced recycling, accumulation of cellular ‘junk’ (clumps of misfolded proteins and damaged cell structures) and reduced cellular function.

 

11. Chronic Inflammation

Chronic inflammation is the increase in baseline levels of inflammation which occurs during aging. It is so pivotal to the aging process it is termed ‘inflammaging’

Chronic inflammation occurs in response to other Hallmarks of Aging which create an environment that promotes excessive inflammation. E.g., increased numbers of senescent cells secrete pro-inflammatory factors which trigger other cells to also become senescent and excrete pro-inflammatory factors.

Chronic inflammation can cause damage to cells and tissues. For example, chronic inflammation stimulates a reduction in immune function. In the skin chronic inflammation degrades collagen, elastin and other scaffolding materials that maintain skin elasticity. In the brain, neuroinflammation contributes to the decline in cognitive function and memory.

 

12. Gut Dysbiosis

The gut microbiome has several important functions:

• Digestion and absorption of nutrients from food
• Protection against pathogens
• Production of important metabolites (e.g., vitamins)

The gut microbiome also communicates with the brain and other organs to influence overall health. Therefore, disruptions to the gut microbiome causes dysbiosis (a major shift in the composition of gut microbiota), which negatively impacts health and contributes to aging.

Studies show aging is associated with key changes to the gut microbiome, including: 

• Reduced diversity of the gut microbiome, with an increase in pro-inflammatory bacteria and a reduction in beneficial bacteria, such as those which strengthen the gut barrier
• Overall reduction in gut barrier integrity and increased gut leakiness
• Ultimately impairing the key functions of the gut and contributing to the development of systemic inflammation (inflammaging)

 

 

The hallmarks of aging are all highly interconnected, they do not occur in isolation. Therefore, to have any impact on aging a multi-target approach is necessary to impact multiple hallmarks simultaneously and support your goal of aging well.

Research is focused on finding tools and molecules to target the Hallmarks of Aging and restore cellular health. Ultimately, the goal is to extend healthspan – the portion of life lived in good health free from disease.

Excitingly, studies continually show NAD+ as a molecule which can positively impact all the Hallmarks of Aging.