What Are the Hallmarks of Ageing? Key Markers and Their Importance
6th Dec 2024
Ageing 101: What are the Hallmarks of Ageing?
Ageing, while unavoidable, is not as inevitable as it once seemed.
Modern research identifies 12 interconnected ageing hallmarks, providing a roadmap for understanding and potentially reversing the ageing process. Each hallmark represents a distinct biological process that explains why we age and that leads to the decline in physical and cellular function over time. They may also provide insights into how we might slow, halt or reverse this process.
So, what are the markers of ageing? This blog post will look at these updated hallmarks proposed by Carlos López-Otín et.al and the promising interventions aimed at them.
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What are the 12 Hallmarks of Ageing?
1. Genomic Instability
DNA damage builds up throughout life due to environmental exposures, DNA replication errors and natural cellular processes. This damage disrupts normal cell function, particularly in stem cells responsible for tissue regeneration. Therapies like enhanced DNA repair enzymes and small molecules aim to slow this damage, maintaining genetic integrity and reducing age-related decline.
Studies also show overexpression of certain DNA repair proteins, such as SIRT6, can extend lifespan in animal models by stabilising the genome.
2. Telomere Attrition
Telomeres cap and protect chromosome ends, but each time our cells divide, they shorten. Critically short telomeres trigger cell death or senescence, preventing tissue renewal. In humans, telomere length is linked with disease susceptibility and lifespan.
Reactivating telomerase, the enzyme that elongates telomeres, has been shown to reverse ageing markers in mice. Gene therapies and telomere-boosting molecules like TA-65 show potential for human applications, as does exercise.
3. Epigenetic Alterations
Epigenetics refers to chemical modifications on DNA and histones that regulate gene expression. Ageing disrupts these patterns, leading to improper gene activation or silencing.
Our Epigenetic clocks use DNA methylation patterns to predict biological age. Interventions like dietary supplements and thymus regeneration protocols have ‘turned back’ these clocks in human studies. Enzymes like SIRT1 and SIRT6, which regulate epigenetics, are also being explored as drug targets for longevity. Dietary nutrients like folate and supplements targeting DNA methylation, are also emerging as strategies.
Further Reading: Factors that Affect Longevity
In our bodies, proteostasis makes sure proteins are correctly folded, maintained and recycled. Ageing overwhelms these systems, leading to toxic protein aggregates involved in neurodegenerative diseases like Alzheimer’s.
Improving the unfolded protein response (UPR) and autophagy pathways to clear misfolded proteins are therapies currently in development, while heat shock proteins (HSPs), molecular chaperones, show promise in improving proteostasis and extending lifespan. You can also boost cellular clean-up systems like autophagy through fasting, supplements or specialised diets.
5. Mitochondrial Dysfunction
Mitochondria generate cellular energy but decline in efficiency with age, leading to reduced bioenergetics and increased oxidative damage. This dysfunction can trigger inflammation and cell death.
NAD+ precursors, such as NR and NMN, boost mitochondrial function and show improvements in muscle strength and cognitive function in clinical trials. Mitohormesis, or controlled mitochondrial stress, through calorie restriction and exercise, stimulates repair mechanisms that extend lifespan in animal models.
6. Deregulated Nutrient-Sensing
The nutrient-sensing network, including insulin/IGF-1 and mTOR pathways, promotes growth in youth but contributes to ageing when overactive.
Caloric restriction, shown to extend lifespan in various species, mimics nutrient-scarcity signals, activating protective pathways and is a possible intervention. Drugs like rapamycin, an mTOR inhibitor, are also being tested for their anti-ageing effects in humans, too.
7. Cellular Senescence
Senescent cells, or ‘zombie cells,’ are when cells stop dividing and start releasing harmful inflammatory signals, damaging neighbouring tissues. These cells build up with age, contributing to chronic diseases and reduced tissue function.
As a breakthrough in senescence, senolytics are drugs designed to selectively destroy senescent cells, rejuvenating tissues and improving healthspan in animal studies.
8. Stem Cell Exhaustion
Ageing drains the pool of stem cells needed to repair and renew tissues, resulting in organ decline and vulnerability to diseases.
Strategies to revitalise stem cells include reprogramming them to a more youthful state and administering stem-cell-based therapies are currently being researched.
Further Reading: Antioxidants and Life Expectancy
9. Altered Intercellular Communication
Chronic inflammation ( inflammaging) disrupts communication between cells and can cause tissue damage. Restoring balance in signalling pathways is important for fighting age-related inflammation.
Anti-inflammatory interventions like IL-10 modulators and dietary omega-3 fatty acids are being studied to reduce inflammaging.
10. Disabled Autophagy
Autophagy declines with age, leading to an accumulation of cellular debris and damaged organelles. Restoring this process has been found to improve cellular health.
Natural compounds like spermidine and pharmaceutical agents, such as rapamycin activate autophagy, are improving healthspan and lifespan in preclinical models.
11. Chronic Inflammation
Known as ‘inflammaging,’ this low-grade, persistent inflammation damages tissues and speeds up ageing. Interventions targeting inflammation could prevent diseases like arthritis, diabetes and cardiovascular conditions.
Drugs like canakinumab, targeting inflammatory pathways, have shown potential in reducing age-related diseases in human trials. Anti-inflammatory diets, omega-3s and compounds like 2-HOBA also neutralise reactive molecules.
12. Dysbiosis
The gut microbiome changes with age, becoming imbalanced, reducing its protective functions and exacerbating inflammation. Restoring a youthful microbial balance is a promising strategy.
Probiotics, prebiotics and faecal microbiota transplants are being explored for their ability to improve gut health and systemic ageing.
Further Reading: Calcium AKG Longevity Benefits
Why Are the Hallmarks of Ageing Important?
The hallmarks of ageing are essential because they provide a clear framework for understanding why and how we age.
By identifying the root causes of ageing — such as DNA damage, cellular stress and inflammation — scientists can develop targeted therapies to slow, prevent or even reverse age-related decline. These hallmarks are not just abstract science; they connect directly to common diseases like Alzheimer's, heart disease and cancer. Tackling them helps extend healthspan, the years of life spent in good health, giving people not just longer lives but better-quality ones.
Nutraceuticals and the Future of Ageing
Emerging nutraceuticals offer new hope for targeting these hallmarks. Supplements like NR and NMN enhance NAD+ levels, supporting cellular repair and energy metabolism. Urolithin A, derived from natural polyphenols, boosts mitophagy — helping cells clean out defective mitochondria.
Studies also highlight compounds like D-ribose, which restores energy production, and 2-HOBA, which combats oxidative stress. Combined with a healthy lifestyle, these innovations may help us reframe ageing as an opportunity rather than a challenge.
End Note
Understanding and targeting these hallmarks of ageing offers a transformative approach to health and longevity. While many therapies are in their infancy, their potential to redefine ageing is immense. By integrating lifestyle changes, pharmacological interventions, and cutting-edge science, we may soon turn the dream of longer, healthier lives into reality.
See how Xandro’s Pure NMN can help improve your NAD+ levels to improve your healthspan.
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