Targeting Cellular Senescence for Enhanced Longevity and Healthier Aging

Introduction

As we age, the quest for longevity and improved quality of life has led scientists to explore innovative strategies that target cellular senescence, a process intricately linked to aging and age-related disease. In this blog, we will delve into the fascinating realm of cellular senescence, discussing its types, effects, and cutting-edge approaches to promote longevity by tackling senescent cells.

What is Senescence?

Cellular senescence is akin to a biological twilight zone, where cells enter a zombie-like state, ceasing division and losing their normal functions (1). This phenomenon is closely tied to aging and the emergence of age-related diseases. 

There are two primary categories of cellular senescence:

1. Replicative senescence: This is triggered by the limited number of times a cell can divide. Each time a cell replicates, the protective caps on the ends of chromosomes, called telomeres, become shorter (Figure 1). When these telomeres become critically short, the cell becomes senescent and can no longer divide.

   

   Figure 1: Simplified diagram showing telomeres, which are protective “caps” of chromosomes. As we age, these caps become shorter and shorter, eventually leading to senescence.

2. Stress-induced senescence: Cells can also enter senescence due to various stress factors, such as DNA damage, oxidative stress, or inflammation. These stressors activate signaling pathways that lead to the arrest of cell division and the acquisition of a senescent phenotype.

Senescent cells are not simply dormant; they can actively contribute to aging and age-related diseases. They secrete molecules, known as the senescence-associated secretory phenotype (SASP), that promote inflammation and tissue dysfunction (2). This chronic inflammation can contribute to the development of various age-related conditions, including cardiovascular disease, cancer, neurodegenerative disorders, and more. 

How Can We Target Senescent Cells for Healthier Aging?

Sirtuin Activating Compounds (STACs)

STACs are a class of compounds known to activate sirtuins, a group of enzymes that play a crucial role in regulating various cellular processes, including aging and longevity. Sirtuins are a protein deacetylase enzyme that removes acetyl groups from other proteins, influencing their activity and function. They are involved in various cellular processes, including DNA repair, metabolism, stress response, and cell survival (4).

Sirtuins are associated with longevity and health span due to their ability to regulate cellular processes that impact aging. Activation of sirtuins has been linked to improved mitochondrial function, enhanced DNA repair mechanisms, and increased stress resistance, all of which contribute to healthier aging (5).

Several compounds and longevity supplements have been identified as potential sirtuin activators, including:

1. Resveratrol is found in grapes, red wine, and certain berries; resveratrol can also mimic the effects of caloric restriction on longevity, promoting cellular health and exhibiting antioxidant and anti-inflammatory properties (6).
2. Fisetin is a natural compound called a flavonoid found in various plant sources. Fisetin is commonly found in fruits, vegetables, and herbs. It has anti-inflammatory and antioxidant attributes that contribute to cellular health and promote DNA repair (7). 
3. Quercetin is also a natural flavonoid compound in various fruits, vegetables, and nuts. Quercetin has anti-cancer, antioxidant, and anti-inflammatory properties that can improve longevity (8). 

Senolytics 

Senolytics are drugs or compounds that potentially target and remove senescent cells from the body (9). The accumulation of senescent cells is associated with various age-related diseases and conditions, including cancer, cardiovascular disease, neurodegenerative disorders, and more (10). The concept behind senolytics is to selectively target and eliminate senescent cells, thereby reducing the burden of these cells in the body and potentially delaying the onset of age-related diseases and promoting longevity. By clearing senescent cells, senolytics aim to improve tissue function, reduce inflammation, and enhance overall health and quality of life. 

Some naturally occurring and some lab-developed compounds have been investigated as potential senolytics:

1. Dasatinib (and Quercetin) are two compounds that have gained attention for their potential as senolytics, which target and eliminate senescent cells. Dasatinib is a cancer drug that has shown promise in clearing senescent cells by disrupting their survival mechanisms. Quercetin may induce cells to undergo programmed cell death (11,12). The combination of these two drugs was the first to be used as senolytics.
2. Spermidine is a naturally occurring polyamine found in all living cells, including humans, animals, plants, and bacteria. Studies suggest spermidine may help eliminate senescent cells by inducing autophagy, which clears out damaged cellular components. By enhancing cellular “clean-up” mechanisms, spermidine may play an important role in removing harmful senescent cells and supporting overall cellular health (13,14).
3. Navitoclax – Originally developed for cancer treatment, navitoclax has shown promise as a senolytic compound. Navitoclax targets BCL-2 family proteins, which regulate cell survival and death. Senescent cells often have elevated levels of these proteins that contribute to their prolonged survival, and navitoclax disrupts this pathway, leading to the selective elimination of senescent cells (15). 
4. Fisetin – Alongside being an STAC, studies have shown that fisetin may help selectively eliminate senescent cells in mice (7). Similar to navitoclax, fisetin also appears to work by disrupting the communication and survival pathways that keep senescent cells alive.

NAD Precursors

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that plays a crucial role in various processes, including NAD production and DNA repair (16). Over the years, NAD precursors have gained attention for their potential role in reducing senescent cells and promoting healthy aging. As cells age, NAD levels tend to decline, contributing to cellular dysfunction and the accumulation of senescent cells (17). NAD precursors, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), are compounds that the body can convert into NAD. By supplementing with NAD precursors, the idea is to boost NAD levels and potentially mitigate some of the effects of cellular aging, including the accumulation of senescent cells. Research suggests that increasing NAD levels through these precursors may help to improve mitochondrial function, enhance DNA repair mechanisms, and support cellular health (18). Some studies in animal models have also shown that NAD precursor supplementation can reduce the number of senescent cells and improve overall health span (18). You can find NAD precursors in several foods; for example, foods containing NR include fruits, vegetables, meat, and milk. Foods that contain NMN include fruits and vegetables like avocados, broccoli, cabbage, edamame, and cucumber (19).

Unfortunately, gaining the right amount of NAD precursors, STACs, or senolytics can be difficult solely through the diet. Moreover, individual responses to these compounds can vary based on genetics, metabolism, and overall health. Furthermore, some compounds mentioned above are only available after speaking to a doctor or as treatments for specific age-related diseases. This is where high-quality supplementation steps in. Supplements that provide controlled and standardized doses of NAD precursors, STACs, or senolytics ensure consistent and potentially more effective results.  MASI provides high-quality premium supplements of resveratrol, NMN, spermidine, and fisetin, allowing you to take control of the senescence levels in your body.

Conclusion

To enhance longevity and combat age-related challenges, the focus on addressing cellular senescence has shown immense potential. The intricate process of senescence, whether due to replication limits or stressors, significantly contributes to aging and related ailments. Promising paths have emerged, like using STACs, senolytics, or NAD precursors to eliminate or rejuvenate senescent cells. Consider incorporating MASI's premium supplements to take control of your journey towards healthier aging. 

Author Biography

This article was written by Dr. Sarah King (PhD). Dr King is a longevity researcher who specialised in molecular and cellular biology, specifically cell aging and fate as related to NAD signalling during her PhD. She is also a senior medical writer for Co-Labb. 

References

1. McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018 Jan 2;217(1):65–77. 
2. Coppé JP, Desprez PY, Krtolica A, Campisi J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu Rev Pathol Mech Dis. 2010 Jan 1;5(1):99–118. 
3. Nousis L, Kanavaros P, Barbouti A. Oxidative Stress-Induced Cellular Senescence: Is Labile Iron the Connecting Link? Antioxidants. 2023 Jun 10;12(6):1250. 
4. Bononi G, Citi V, Lapillo M, Martelli A, Poli G, Tuccinardi T, et al. Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives. Molecules. 2022 Oct 3;27(19):6535. 
5. Grabowska W, Sikora E, Bielak-Zmijewska A. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017 Aug;18(4):447–76. 
6. Meng T, Xiao D, Muhammed A, Deng J, Chen L, He J. Anti-Inflammatory Action and Mechanisms of Resveratrol. Molecules. 2021 Jan 5;26(1):229. 
7. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18–28. 
8. Cui Z, Zhao X, Amevor FK, Du X, Wang Y, Li D, et al. Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism. Front Immunol. 2022 Jul 22;13:943321. 
9. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020 Nov;288(5):518–36. 
10. Zhang L, Pitcher LE, Yousefzadeh MJ, Niedernhofer LJ, Robbins PD, Zhu Y. Cellular senescence: a key therapeutic target in aging and diseases. J Clin Invest. 2022 Aug 1;132(15):e158450. 
11. Kim SG, Sung JY, Kim JR, Choi HC. Quercetin-induced apoptosis ameliorates vascular smooth muscle cell senescence through AMP-activated protein kinase signaling pathway. Korean J Physiol Pharmacol. 2020;24(1):69. 
12. Saccon TD, Nagpal R, Yadav H, Cavalcante MB, Nunes AD de C, Schneider A, et al. Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice. Anderson RM, editor. J Gerontol Ser A. 2021 Oct 13;76(11):1895–905. 
13. De Cabo R, Navas P. Spermidine to the rescue for an aging heart. Nat Med. 2016 Dec;22(12):1389–90. 
14. Ghosh I, Sankhe R, Mudgal J, Arora D, Nampoothiri M. Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders. Neuropeptides. 2020 Oct;83:102083. 
15. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Pirtskhalava T, Giorgadze N, et al. Identification of a novel senolytic agen, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 15:428–35. 
16. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. 2021;22:119–41. 
17. Covarrubias AJ, Kale A, Perrone R, Lopez-Dominguez JA, Pisco AO, Kasler HG, et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat Metab. 2020 Nov 16;2(11):1265–83. 
18. Reiten OK, Wilvang MA, Mitchell SJ, Hu Z, Fang EF. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mech Ageing Dev. 2021 Oct;199:111567. 
19. Poljsak B, Kovač V, Milisav I. Healthy Lifestyle Recommendations: Do the Beneficial Effects Originate from NAD+ Amount at the Cellular Level? Myers JN, editor. Oxid Med Cell Longev. 2020 Dec 12;2020:1–12. 
20. Palmer RD, Elnashar MM, Vaccarezza M. Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging. AGING Med. 2021 Sep;4(3):214–20.