Senolytics: Revolutionising the Approach to Healthy Ageing by Targeting Senescent Cells

Hallmarks of Ageing 2/12

As the world's population ages, the quest for longevity and a healthier, vibrant life in later years becomes increasingly important. A crucial player in this pursuit is the understanding of senescent cells, often termed 'zombie cells,' and the emerging field of senolytics. These breakthroughs offer promising avenues for enhancing health during ageing.

The Science of Ageing and Senescent Cells:

Age-related decline in organ function raises questions about cellular efficiency over time. Moorhead and Hayflick's 1960s discovery of the "Hayflick limit" at the Wistar Institute revealed that cells, like fibroblasts, have a natural replication limit, crucial in preventing cancerous growth. However, cells that cease dividing and don't die become senescent, adopting abnormal shapes and releasing harmful substances, thus contributing to the ageing process and diseases.

‘Zombie cells' stop dividing and performing their duties as healthy cells should, yet they refuse to die too. Instead, they hang around, releasing harmful substances that can damage nearby healthy cells, turning them into zombie cells, causing inflammation and disrupting the harmony in your body.

Why Senescent Cells are Problematic:

Senescent cells stop performing essential functions and refuse to die, releasing substances that harm healthy cells, leading to ageing-related problems, from wrinkles to severe health issues.

Combating Senescent Cells with Senolytics:

Senolytics selectively target and eliminate senescent cells, offering the potential to mitigate ageing and age-related diseases. Lifestyle changes, dietary practices, and certain drugs support this.

Lifestyle and Diet Hacks for Managing Senescence:

• Intermittent Fasting: Reduces oxidative stress and improves cellular autophagy. That means an extra push to remove abnormal cells that have not gone through the normal process of apoptosis or programmed cell death. Work by Dr Longo has shown that targeted cyclical deep fasting can potentially even remove cancerous cells.
• Regular Exercise: A mix of aerobic and resistance training enhances cellular health.
• Reducing Stress: Mindfulness, meditation, and yoga can manage stress, slowing cellular ageing.
• Adequate Sleep: Essential for cellular repair and maintenance. Particularly important in the brain. The clean-up driven by the glymphatic system works at night while we sleep.
• Antioxidant-Rich Diet: Foods like berries, nuts, and greens limit the formation of senescent cells. Less damage means fewer zombie cells.

Senolytic Supplements:

Senolytic supplements, often nutrient-rich, target senescent cells. Studies suggest they extend lifespan and maintain cellular balance.

The Growing Popularity of Senolytic Supplements:

With an increased focus on healthy ageing, senolytic supplements have surged in popularity. These supplements, rich in nutrients, target the ageing cells – the senescent cells – that have ceased functioning correctly. By eliminating these cells, senolytics may help reduce the accumulation of harmful proteins that increase inflammation and contribute to various chronic illnesses. This action is critical because chronic diseases such as cardiovascular ailments, metabolic dysfunction, and certain cancers have been linked to the buildup of senescent cells.

The Future of Ageing and Health:

The WHO estimates that the global population over 60 will double by 2050. This demographic shift underscores the importance of understanding and managing age-related health issues. Senolytics offer a groundbreaking approach to support this growing demographic, potentially reducing the prevalence of chronic age-related diseases and improving quality of life.

In-Depth Look at Senolytic Agents:

1. Quercetin:

Quercetin is a naturally occurring flavonoid found in many fruits and vegetables, like onions, broccoli, apples, and cherries. It has garnered attention for its potential as a senolytic agent.

Mechanism of Action:

• Senolytic Activity: Quercetin targets senescent cells by disrupting their survival pathways. One of the key studies (Hickson et al., 2019) involving participants with diabetic kidney disease showed that a combination of Quercetin and Dasatinib significantly reduced senescent cells in fatty tissues.
• Anti-Inflammatory Effects: Quercetin is known to reduce the secretion of inflammatory cytokines. This is crucial because senescent cells often release pro-inflammatory factors contributing to tissue damage and ageing.
• Cardiovascular Protection: Quercetin may also protect the heart, as noted in a review, by preventing age-related heart failure. This effect is likely due to its antioxidant and anti-inflammatory properties.

Recommended dosage: 400-800mg quercetin per day

2. Fisetin:

Fisetin is a flavonoid found in strawberries, apples, and other fruits. It has shown promising results as a senolytic.

Mechanism of Action:

• Clearing Senescent Cells: Fisetin helps destroy senescent cells, particularly in fatty tissues, as demonstrated in studies involving human adipose tissue and aged mice (Yousefzadeh et al., 2018).
• Anti-Inflammatory Properties: Fisetin inhibits the secretion of inflammatory cytokines. This action was observed in studies where fisetin reduced inflammation in LPS-induced RAW264.7 cells (Sun et al., 2021).
• Promoting Autophagy: Fisetin can induce autophagy, a process where cells clear out damaged components, which may further aid in reducing senescent cells.

Recommended dosage: 200-400mg fisetin per day

3. Curcumin:

Curcumin, the active compound in turmeric, has a wide array of health-promoting properties and is emerging as a potential senolytic.

Mechanism of Action:

• Antioxidant Activity: Curcumin exhibits strong antioxidant capabilities, which can neutralise free radicals and reduce oxidative stress, a key factor in ageing.
• Telomere Protection: Studies suggest that curcumin may increase the activity of enzymes that maintain telomere length, thereby potentially reducing cellular ageing (Pan et al., 2017).
• Lifespan Extension: Animal studies have shown that curcumin can increase the lifespan of certain species by enhancing cellular health and function.

Recommended dosage: 1000-2500mg turmeric with piperine to increase bioavailability

4. Milk Thistle (Silybum marianum):

Milk Thistle is known for its liver-supporting properties but also shows promise as a senolytic.

Mechanism of Action:

• Senescent Cell Clearance: A study involving human skin cells found that milk thistle extract could eliminate senescent cells, promoting the proliferation of younger cells (Woo et al., 2021).
• Antioxidant Properties: Milk Thistle acts as an antioxidant, helping to protect cells from oxidative damage.
• Anti-Ageing Effects: The herb’s potential to rejuvenate cells and prevent premature ageing, especially in skin cells, is a notable aspect of its senolytic capabilities.

Recommended dosage: 100-300mg of silymarin per day

Other non-senolytic supplements

5. Spermidine:

Spermidine is a polyamine compound found in various foods like aged cheese, mushrooms, soy products, and whole grains. It has gained interest for its potential role in promoting cellular health and longevity.

Mechanism of Action:

• Autophagy Induction: Spermidine is known primarily for its ability to induce autophagy, a cellular cleansing process that removes damaged components and helps in cellular rejuvenation.
• Cellular Longevity: By promoting autophagy, spermidine can potentially extend the lifespan of cells, thereby contributing to overall health and longevity. This effect is supported by studies showing that spermidine supplementation can extend the lifespan in various model organisms.
• Cardiovascular Health: Spermidine may also benefit heart health by improving cardiac autophagy, reducing hypertension, and mitigating age-related decline in heart function.

Dosage: 500-700mg spermidine per day. Recommend cycling for 2-3 months at a time with an equal break afterwards.

6. Resveratrol:

Resveratrol, a compound found in grapes, berries, and peanuts, is known for its anti-aging properties.

Mechanism of Action:

• Sirtuin Activation: Resveratrol is noted for activating sirtuins, a family of proteins believed to play a role in ageing processes. Sirtuins can influence cellular processes like DNA repair and gene expression, which are crucial for longevity.
• Antioxidant Effects: Like many other compounds on this list, resveratrol functions as an antioxidant, reducing oxidative stress and potentially protecting cells from premature ageing and damage.
• Anti-Inflammatory Properties: Resveratrol can modulate inflammation, a key factor in the ageing process and the development of age-related diseases.

Dosage: 300-500mg trans-resveratrol per day. Take with yoghurt or olive oil to increase absorption due to poor bioavailability.

7. Dasatinib and Quercetin Combination:

This combination has been studied for its potent senolytic effects, particularly in clearing senescent cells.

Mechanism of Action:

• Targeting Senescent Cells: Dasatinib, an anti-cancer drug, and Quercetin, a natural flavonoid, work synergistically to target and eliminate senescent cells. Dasatinib primarily targets senescence pathways associated with the tyrosine kinase protein, while Quercetin disrupts the survival pathways of senescent cells.
• Reduction of Senescent Cell Burden: Studies, including those by Hickson et al. (2019), have shown that this combination can significantly reduce the number of senescent cells, particularly in adipose tissue.
• Anti-Inflammatory and Anti-Fibrotic Effects: Reducing senescent cells can lead to decreased secretion of pro-inflammatory and pro-fibrotic factors, contributing to a reduction in tissue inflammation and fibrosis, common in ageing-related diseases.

Dosage: Dasatinib is a powerful cancer medication and should only be used with a specialist with experience in a carefully monitored setting.

Summary

Senolytics are a class of compounds targeting senescent cells, known as 'zombie cells', which accumulate in tissues as we age and contribute to age-related decline. These compounds, including fisetin, quercetin, curcumin, spermidine, resveratrol, and others, have shown promise in reducing senescent cell burden and associated inflammation. Lifestyle and diet modifications, like intermittent fasting, regular exercise, stress reduction, adequate sleep, and an antioxidant-rich diet, complement senolytics in managing cellular senescence.

Drug and research in senolytics latest Dec 2023

In the field of senolytic research, several companies are actively exploring treatments targeting senescent cells. Unity Biotechnology is a notable player, having conducted a Phase 2 study (UBX0101) and working on a Phase 1 study (UBX1325)​​. The industry is evolving from first-generation senolytics, like Dasatinib and Navitoclax, which had off-target effects, to second-generation therapies focused on improved selectivity through novel modalities and delivery methods​​.

Other companies with promising work in this area include FoxBio, Senolytic Therapeutics, Numeric Biotech, and Rubedo Life Science, which is expected to enter clinical trials soon​​. Additionally, Senolytic Therapeutics, Senisca, Atropos Therapeutics, and Dorian Therapeutics are developing senomorphic pipelines, focusing on slowing down senescence rather than directly killing senescent cells​​. The industry's future hinges on the success of these diverse approaches, indicating a robust and evolving landscape for senolytic research and potential therapies​.

Build your senolytic stack with humanpeople:

1. Quercetin

2. Curcumin

3. Milk Thistle (Silybum marianum)

4. Spermidine

5. Resveratrol

 

References:

 

1. Yamaura K, Nelson AL, Nishimura H, et al. Therapeutic potential of senolytic agent quercetin in osteoarthritis: A systematic review and meta-analysis of preclinical studies. Ageing Res Rev. 2023;90:101989. 
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3. Shao Z, Wang B, Shi Y, et al. Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis. Osteoarthritis Cartilage. 2021;29(3):413-422. 
4. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28. doi:10.1016/j.ebiom.2018.09.015
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12. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease 
13. UNITY Biotechnology Announces Positive 48-Week Results from Phase 2 BEHOLD Study of UBX1325 in Patients with Diabetic Macular Edema
14. A Review of Senolytics Biotech Companies
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