In this article, we cover the topic of resilience to molecular damage and stress. We’ll explore how this resilience can be nurtured through various interventions, including supplements and lifestyle modifications. We will also discuss the intricate mechanisms of FXR and bile acid signaling, the adaptive Heat Shock Response (HSPs and HSF), the phenomenon of mitohormesis and UPRmt, the influential Nrf2 pathway, and the critical role of iron in the aging process.
This is the second article in our five-part “The Pathways of Aging” series, where we introduce the most important pathways and concepts in aging research. Each article addresses a major category according to the underlying biology.
- Growth Pathways and Nutrient Sensing
- Resilience to Molecular Damage and Stress
- Repair and Recycling
- Rejuvenation of Cells, Tissues, and Stem Cells
- Metabolic Health
Table of Contents
Bile Acid Signaling and its Implications for Healthspan and Disease Resistance
Bile acid signaling is a very interesting and often neglected pathway consistently activated in many long-lived mice.
Farnesoid X receptor (FXR) is the receptor that is activated by bile acids to promote the expression of detoxification enzymes. This receptor is elevated in long-lived growth hormone knockout mice (Bartke and Sun 2019). Many attempts have been made to target this pathway directly. However, bile acid mimetics (molecules that mimic bile acids), even though they may benefit invertebrates (Morshead et al. 2020, Groen et al. 2013), have never resulted in mouse lifespan extension, suggesting this might be a minor pathway more relevant to health span and cancer resistance than to lifespan (Strong et al. 2016).
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Heat Shock Response: Protecting Proteins and Prolonging Lifespan
HSF1 is a transcription factor that binds heat shock elements (HSEs) to activate the expression of so-called chaperone proteins like HSP70 or HSP90 (Labbadia and Morimoto 2015). These chaperones help to assemble, fold, and maintain proteins in a functional state even under circumstances that would otherwise destabilize them (e.g., accumulation of toxic proteins or elevated body temperature).
Why does the heat shock response matter? Protein aggregation is considered a hallmark of aging (Labbadia and Morimoto 2015), particularly of neurodegenerative diseases (e.g., Alzheimer’s disease), and reduced chaperone expression accompanies aging (Jurivich et al. 2020). In contrast, HSF1 and/or chaperone levels are higher in long-lived rodents like the naked mole rat and in long-lived bats (Rodriguez et al. 2016, Pride et al. 2015, Chionh et al. 2019). Further underscoring the benefits of an activated heat shock response, researchers recently found that overexpressing a certain heat shock protein closely related to human HSPs extends the lifespan of worms (Alexander et al. 2022).
However, there is also a dark side to the heat shock response because it is co-opted in some cancers. Therefore, the net benefit of inducing HSPs in humans remains unclear, although it will likely be beneficial.
The safest and most natural way to elevate heat shock proteins is through regular exercise and sauna usage (Henstridge et al. 2016, Patrick and Johnson 2021) or through adaptogens like ginger and rhodiola rosea extracts (Sugimoto et al. 2021, Hernández‐Santana et al. 2014) – both of which are found in NOVOS Core.
NOVOS Core Ingredients for Heat Shock Response:
Cellular Stress Response and the Benefits of Hormesis and Mitohormesis
Cells can adapt to repeated stressors. When a cell is subjected to oxidative or folding stress, for example, it will turn up the volume on a genetic program to defend against further related insults. This kind of anticipatory adaptation is called hormesis and can be beneficial (e.g., stress due to exercise or mild oxidative stress leading to upregulation of Nrf2). However, not all stress is beneficial, and too much will be harmful since hormesis only occurs in the lower ranges of stress exposure.
Although less well understood, such stress adaptation also occurs on the mitochondria level, which is called mitohormesis (Yun and Finkel 2014). The unfolded protein response of mitochondria (UPRmt) is one well-described kind of mitohormesis.
A mitochondrial stress, often depolarization at the mitochondrial membrane, mitochondrial ROS (highly reactive and damaging molecules formed with oxygen at their foundation), or misfolding inside mitochondria, signals back to the cell nucleus to turn on protective genes (“retrograde signaling”). This response can include the creation of new mitochondria and the production of mitochondrial heat shock proteins. Some putative “retrograde” signals returning to the nucleus are the proteins ATF4 and ATF5. Stressed cells also secrete mitochondrial hormones, mitokines, like FGF21 and GDF15 (Forsström et al. 2019). Intriguingly, ATF4 is elevated in many long-lived mouse models (Li et al. 2014), and over-expression of FGF21 leads to large and robust lifespan extension in mice (Zhang et al. 2012).
In humans, circulating FGF21 levels are elevated by exercise and diets low in protein (Qian et al. 2022), and FGF21 levels are elevated in vegans compared to omnivores (Castaño-Martinez et al. 2019).
Many drugs and nutraceuticals like glucosamine (Weimer et al. 2014, Kumar et al. 2021), metformin (De Haes et al. 2014), or pterostilbene (Suárez-Rivero et al. 2022) are thought to act through hormesis or mitohormesis. NOVOS Core contains both glucosamine and pterostilbene.
NOVOS Core Ingredients for Cellular Stress Response:
The Nrf2 Pathway: From Biomolecule Protection to Extended Lifespan
The Nrf2 pathway is chiefly responsible for upregulating multistress resistance, including resistance to oxidative and many other stressors that damage our biomolecules.
A preponderance of evidence suggests that Nrf2 is a key regulator of longevity and, even more so, cancer. Across species, the longer-lived animals express higher levels of Nrf2 or Nrf2 activating proteins (Lewis et al. 2015), long-lived mice express high levels of Nrf2 target genes (Leiser and Miller 2010), mice lacking functional Nrf2 are sensitive to cancer and die early, and, at least in some studies, the anti-cancer benefits of caloric restriction depend on Nrf2 (Pearson et al. 2008, Pomatto et al. 2020). Finally, the specific Nrf2 activator found in broccoli and sprouts – sulforaphane – extends lifespan in mice and invertebrates, and it also promotes the detoxification of carcinogens in multiple human studies (Kensler et al. 2012, Chen et al. 2019, Bose et al. 2020).
How can we activate Nrf2 to live longer? Apart from so-called isothiocyanates like sulforaphane, other activators include a diverse array of phytochemicals that induce transient stress leading to “hormesis” — for example, two components of NOVOS Core: pterostilbene (Zhou et al. 2019) and a chemical found in rhodiola rosea called salidroside (Li et al. 2019).
NOVOS Core Ingredients for Nrf2 Activation:
The Relationship between Iron Levels, Aging, and Cancer
Iron can promote oxidative stress, protein and DNA damage via the so-called Fenton reaction. Older individuals may be at particular risk for this harmful effect because iron was found to accumulate in several tissues with aging. Thus it should come as no surprise that lowering your iron levels can protect against cancer, according to recent studies. You can read more on this topic in our article on iron and aging.
A Journey Through Molecular Damage and Stress Pathways
This article took an in-depth look at molecular damage and stress, uncovering the intricate pathways that enable organisms to withstand the ravages of time. From the overlooked yet essential bile acid signaling pathway to the heat shock response and its protective chaperone proteins to the remarkable cellular stress response mechanisms of hormesis and mitohormesis and the pivotal role of the Nrf2 pathway in multistress resistance, we have explored how these pathways contribute to health span and disease resistance.
These pathways are not only crucial for longevity but also hold the potential for combatting diseases like cancer. By understanding and harnessing the power of these pathways, we can explore novel avenues for interventions that promote resilience and enhance our well-being.
In the following article of this series, we look at cellular repair and recycling pathways, exploring how these mechanisms contribute to the longevity of species by efficiently removing accumulated damage.
Kamil Pabis
Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.
Kamil received his MSc degree from the University of Vienna and is presently pursuing a PhD degree at the National University of Singapore. In addition, Kamil also hosts the Aging Science Podcast by VitaDAO and is an avid science communicator on twitter @Aging_Scientist.
References
References – FXR and bile acid signaling
Bartke A., Sun L. (2019) Early Life Programming of Aging in Genetically Long-Lived Mice. In: Vaiserman A. (eds) Early Life Origins of Ageing and Longevity. Healthy Ageing and Longevity, vol 9. Springer, Cham. https://doi.org/10.1007/978-3-030-24958-8_3
Strong, Randy, et al. “Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer.” Aging cell 15.5 (2016): 872-884.
Groen, Albert K., and Folkert Kuipers. “Bile acid look-alike controls life span in C. elegans.” Cell metabolism 18.2 (2013): 151-152.
Morshead, Mackenzie L., et al. “Caenorhabditis Intervention Testing Program: the farnesoid X receptor agonist obeticholic acid does not robustly extend lifespan in nematodes.” Micropublication Biology 2020 (2020).
References – heat shock response (HSPs and HSF)
Labbadia, Johnathan, and Richard I. Morimoto. “The biology of proteostasis in aging and disease.” Annual review of biochemistry 84 (2015): 435.
Jurivich, Donald A., et al. “Multifactorial attenuation of the murine heat shock response with age.” The Journals of Gerontology: Series A 75.10 (2020): 1846-1852.
Rodriguez, Karl A., et al. “Determinants of rodent longevity in the chaperone-protein degradation network.” Cell Stress and Chaperones 21.3 (2016): 453-466.
Pride, Harrison, et al. “Long-lived species have improved proteostasis compared to phylogenetically-related shorter-lived species.” Biochemical and biophysical research communications 457.4 (2015): 669-675.
Chionh, Yok Teng, et al. “High basal heat-shock protein expression in bats confers resistance to cellular heat/oxidative stress.” Cell Stress and Chaperones 24.4 (2019): 835-849.
Alexander, Courtney Carroll, et al. “HspB1 Overexpression Improves Life Span and Stress Resistance in an Invertebrate Model.” The Journals of Gerontology: Series A 77.2 (2022): 268-275.
Henstridge, Darren C., Mark A. Febbraio, and Mark Hargreaves. “Heat shock proteins and exercise adaptations. Our knowledge thus far and the road still ahead.” Journal of applied physiology 120.6 (2016): 683-691.
Patrick, Rhonda P., and Teresa L. Johnson. “Sauna use as a lifestyle practice to extend healthspan.” Experimental Gerontology 154 (2021): 111509.
Sugimoto, Naotoshi, et al. “Ginger facilitates cell migration and heat tolerance in mouse fibroblast cells.” Molecular medicine reports 23.4 (2021): 1-1.
Hernández‐Santana, Aaron, et al. “A Rhodiola rosea root extract protects skeletal muscle cells against chemically induced oxidative stress by modulating heat shock protein 70 (HSP70) expression.” Phytotherapy Research 28.4 (2014): 623-628.
References – mitohormesis and UPRmt
Yun, Jeanho, and Toren Finkel. “Mitohormesis.” Cell metabolism 19.5 (2014): 757-766.
Musci, Robert V., Karyn L. Hamilton, and Melissa A. Linden. “Exercise-induced mitohormesis for the maintenance of skeletal muscle and healthspan extension.” Sports 7.7 (2019): 170.
Forsström, Saara, et al. “Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions.” Cell metabolism 30.6 (2019): 1040-1054.
Li, Weiquan, Xinna Li, and Richard A. Miller. “ATF 4 activity: a common feature shared by many kinds of slow‐aging mice.” Aging cell 13.6 (2014): 1012-1018.
Zhang, Yuan, et al. “The starvation hormone, fibroblast growth factor-21, extends lifespan in mice.” elife 1 (2012): e00065.
Castaño-Martinez, Teresa, et al. “Methionine restriction prevents onset of type 2 diabetes in NZO mice.” The FASEB Journal 33.6 (2019): 7092-7102.
Weimer, Sandra, et al. “D-Glucosamine supplementation extends life span of nematodes and of ageing mice.” Nature communications 5.1 (2014): 1-12.
Kumar, Raushan, Komal Saraswat, and Syed Ibrahim Rizvi. “Glucosamine displays a potent caloric restriction mimetic effect in senescent rats by activating mitohormosis.” Rejuvenation Research 24.3 (2021): 220-226.
De Haes, Wouter, et al. “Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2.” Proceedings of the National Academy of Sciences 111.24 (2014): E2501-E2509.
Suárez-Rivero, Juan M., et al. “Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases.” Frontiers in pharmacology 13 (2022): 862085.
References – Nrf2
Zhou, J.; Ci, X.; Ma, X.; Yu, Q.; Cui, Y.; Zhen, Y.; Li, S. Pterostilbene Activates the Nrf2-Dependent Antioxidant Response to Ameliorate Arsenic-Induced Intracellular Damage and Apoptosis in Human Keratinocytes. Front. Pharmacol. 2019, 10, 497.
Lewis, Kaitlyn N., et al. “Regulation of Nrf2 signaling and longevity in naturally long-lived rodents.” Proceedings of the National Academy of Sciences 112.12 (2015): 3722-3727.
Leiser, Scott F., and Richard A. Miller. “Nrf2 signaling, a mechanism for cellular stress resistance in long-lived mice.” Molecular and cellular biology 30.3 (2010): 871-884.
Pearson, Kevin J., et al. “Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction.” Proceedings of the National Academy of Sciences 105.7 (2008): 2325-2330.
Chen, Jian-Guo, et al. “Dose-dependent detoxication of the airborne pollutant benzene in a randomized trial of broccoli sprout beverage in Qidong, China.” The American Journal of Clinical Nutrition 110.3 (2019): 675-684.
Kensler, Thomas W., et al. “Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China.” Carcinogenesis 33.1 (2012): 101-107.
Bose, Chhanda, et al. “Sulforaphane prevents age‐associated cardiac and muscular dysfunction through Nrf2 signaling.” Aging Cell 19.11 (2020): e13261.
Li, Ruru, et al. “Salidroside protects dopaminergic neurons by preserving complex I activity via DJ-1/Nrf2-mediated antioxidant pathway.” Parkinson’s Disease 2019 (2019).
Pomatto, Laura CD, et al. “Deletion of Nrf2 shortens lifespan in C57BL6/J male mice but does not alter the health and survival benefits of caloric restriction.” Free Radical Biology and Medicine 152 (2020): 650-658.
