Researchers have discovered different pathways and concepts underpinning the complex aging phenomenon. In this series of articles, we’ll look at the various biological pathways that contribute to the 12 hallmarks of aging and shape our overall understanding of the aging process.
This article explores the key components of growth pathways and nutrient sensing, shedding light on their roles in promoting longevity and influencing overall health. We’ll look at the FoxO transcription factors, IGF-1, mTOR, H2S and ATF4, and AMPK, unraveling their connections to aging and potential interventions to enhance healthspan.
This is the first 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
The FoxO Pathway and its Impact on Longevity:
The FoxO transcription factors (proteins that bind to specific sequences of DNA to control the transcription of genetic information from DNA to RNA), especially FoxO3 and FoxO1, are critical mediators of longevity. Normally, the pancreas’ insulin and insulin-like growth factor 1 (IGF-1) secretion during carbohydrate and protein consumption keeps FoxOs inactive and sequestered outside the cell nucleus. During limited nutrient availability (e.g., during fasts or ketosis), however, FoxO transcription factors move into the nucleus to activate genes that promote autophagy (a healthy process whereby the body feeds upon itself; recycling of cellular components from older, damaged cells) and stress resistance, while inhibiting mTOR signaling (a stimulator of growth; more on mTOR below) (Du and Zheng 2021).
Although the FoxO pathway has drawn less attention than growth hormone (GH / HGH), Insulin-like growth factor 1 (IGF-1), or mTOR, several studies nonetheless support the purported health benefits. For example, we know that genetically removing FoxO3 prevents lifespan extension in calorie-restricted mice (Shimokawa et al. 2015) and that human FoxO3a is among the strongest candidate genes associated with extreme survival in the longest-lived humans (Revelas et al. 2018).
As far as increasing FoxO transcription factors is concerned, flavonoids like fisetin, which is found in NOVOS Core, appears to be a dual inducer of both FoxO and Nrf2, as these pathways share many target genes, and both respond to hormetic stresses (Pallauf et al. 2017).
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IGF-1: The Link Between Nutrition, Growth Hormones, and Aging
The body can sense protein and nutrient levels via the brain’s hypothalamic pituitary axis. IGF-1 is an anabolic peptide hormone that manages the effects of growth hormones on the body.
Fasting and starvation, and in humans, low protein intake specifically decrease IGF-1 levels, which may be beneficial (Kazemi et al. 2020). Further, supplements like Pterostilbene (McCormack & McFadden, 2013), Rhodiola rosea (Teng et al., 2022), Fisetin (Kubo et al., 2020; Park et al., 2022), glucosamine (Sakai & Clemmons, 2003), vitamin C (Reynolds, 2022) and ginger (Xu et al., 2022) could help in regulating IGF-1 production to increase lifespan and healthspan directly or indirectly.
For example, high IGF-1 levels during development may explain why taller people or larger dogs and cats die younger (Bartke 2012, Miller and Austad 2006). Furthermore, not only do dwarf mice with reduced GH/IGF-1 signaling live longer but offspring from very long-lived parents also have alterations in the GH/IGF-1 system, suggesting this pathway may be relevant in humans as well (Vitale et al. 2019). Research indicates that elevated levels of GH/IGF-1 may increase the risk of cancer (Grimberg 2003).
NOVOS Core Ingredients for IGF-1 Regulation:
mTOR: The Powerhouse Pathway Shaping Aging and Longevity
The mechanistic target of rapamycin (mTOR) pathway is often playfully referred to as the pathway that regulates everything. The mTOR protein complex is indeed a master sensor for nutrient levels inside the cells that affects a myriad of other processes and pathways. It can sense low amino acid levels at the lysosome (the cell’s major recycling hub) and low ATP levels (the energy currency of the cell) via crosstalk with the AMPK pathway (more on this in a bit), then in response, downregulate energy-demanding processes like the creation of new proteins, cells, and fats (Papadopoli et al. 2019).
The mTOR pathway is one of the most famous (anti-)aging pathways. Such a reputation is well-deserved since it is also the best-established and most potent. Suppressing mTOR extends the lifespan of yeast, worms, and flies (Bjedov et al. 2010, Papadopoli et al. 2019). However, the most compelling evidence linking mTOR and aging comes from elegant mouse studies that found mTOR inhibition extended lifespan even when initiated in middle-aged mice (Harrison et al. 2009). Importantly from a translational side, human studies have shown that suppressing mTOR upregulates antiviral responses (Mannick et al. 2021), which could be indicative of a rejuvenated immune system.
However, with great power also comes great risk. Strong and sustained suppression of mTOR signaling will impair immunity and might also impair muscle mass.
Some biohackers experiment with low-dose rapamycin–a prescription drug from which mTOR is named, because it downregulates it–or higher pulsed dosages every one to two weeks. While this approach holds promise, there are not enough studies to conclude that it is safe.
Presently, there are only a few safe ways to decrease mTOR signaling for optimal health over the long haul. Although the issue remains debated, low-to-moderate protein diets, especially those low in animal-derived branched-chain amino acids (BCAAs), could benefit longevity when started before old age (Richardson et al. 2021, Naghshi et al. 2020, Green et al. 2021). Supplements that have shown moderate mTOR inhibitory effects include curcumin, epigallocatechin gallate (EGCG) found in green tea (Zhou et al. 2010), as well as Rhodiola rosea (Liu et al., 2012), Alpha-ketoglutarate (Su et al., 2019), vitamin C (Qin et al., 2023) and ginger (Hung et al., 2009), all of which are found in NOVOS Core.
NOVOS Core Ingredients with mTOR Inhibitory Effects:
H2S and ATF4: Exploring their Role in Longevity and Cellular Health
Hydrogen sulfide (H2S) is a gas that, at high levels, not only smells like rotten eggs but is also deadly. Thus it surprised many when scientists discovered that the body produces low levels of H2S that are supposedly beneficial. In fact, hydrogen sulfide is elevated in the tissues of long-lived mice under caloric restriction and may contribute to suppressing IGF-1 levels and to elevating Nrf2 signaling (Hine et al. 2017, Hine et al. 2015). The longevity protein ATF4 found to be elevated in many slow-aging mice (Li et al. 2014) is most likely responsible for the increased production of H2S in these animals.
If you want to boost your H2S levels, add more garlic, broccoli, and sprouts to your diet. Allicin, the active compound in garlic, and sulforaphane, the active compound in broccoli and sprouts, may be able to elevate hydrogen sulfide in humans safely (Rose et al. 2021). Check out this article to get an in-depth understanding of the different components of a longevity-promoting diet.
AMPK: The Cellular Energy Guardian for Longevity and Health
The AMPK protein, also called AMP-activated protein kinase, can sense the energy levels inside cells by surveilling the ratio of AMP (adenosine monophosphate; one phosphate group) to ATP (adenosine triphosphate; three phosphate groups, and the ideal energy currency of a cell), allowing the cell to adapt and survive under low nutrient or energy conditions (Burkewitz et al. 2014, youtube-video). Unsurprisingly, exercise and caloric restriction are the prototypical AMPK inducers since they decrease cellular energy levels — a beneficial “hormetic” stress that makes you stronger.
Activation of AMPK promotes autophagy and the creation of new mitochondria (the cell’s power plants), inhibits mTOR, and reduces the creation of fatty acids, cholesterol, and proteins (Timm and Tyler 2020). This sounds really beneficial, and there is emerging evidence for the anti-aging benefits of AMPK.
Genetic overexpression of AMPK extends the lifespan of fruit flies (Ulgherait et al. 2014) and nematode worms, whereas loss of AMPK shortens the lifespan of worms (Apfeld et al. 2004). Unfortunately, we do not have similar experiments in mice. Still, we know that aging leads to reduced or less efficient activation of AMPK (Salminena et al. 2016), which can be offset with nutraceuticals and drugs, leading to various health benefits.
For example, (re-)activation of AMPK using the anti-diabetic drug metformin extends health span in mice (Martin-Montalvo et al. 2013), and diabetic patients treated with metformin had lower cancer rates than even non-diabetics (Campbell et al. 2017). Other natural activators include the longevity hormone FGF21 (Salminen et al. 2017); pterostilbene (Martina et al. 2021, Yen-Chun et al. 2021); gingerols (Bo et al. 2022, Alieh et al.), which are phytochemicals found in ginger; and L-theanine (Xialing et al. 2022, Ling et al. 2021). The latter three are all part of NOVOS Core.
NOVOS Core Ingredients for AMPK Activation:
Journeying Through Growth Pathways and Nutrient Sensing
The study of growth pathways and nutrient sensing provides valuable insights into the intricate mechanisms underlying the aging process. From the pivotal role of FoxO transcription factors in promoting longevity to the influence of IGF-1, mTOR, H2S and ATF4, and AMPK, these pathways offer exciting avenues for interventions to enhance healthspan & lifespan.
In the following article of this series, we explore how resilience to molecular damage and stress is a shared characteristic of many long-lived species and how it can be promoted through supplements and lifestyle, among other things.
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 – FOXO
Du, Shuqi, and Hui Zheng. “Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.” Cell & Bioscience 11.1 (2021): 1-17.
Revelas, Mary, et al. “Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity.” Mechanisms of ageing and development 175 (2018): 24-34.
Shimokawa, Isao, et al. “The life‐extending effect of dietary restriction requires F oxo3 in mice.” Aging cell 14.4 (2015): 707-709.
Pallauf, Kathrin, et al. “Flavonoids as putative inducers of the transcription factors Nrf2, FoxO, and PPARγ.” Oxidative Medicine and Cellular Longevity 2017 (2017).
References – IGF-1
Miller RA, Austad SN. Growth and aging: why do big dogs die young? In: Masoro EJ, Austad SN, editors. Handbook of the Biology of Aging. 6th ed. San Diego, CA: Academic Press; 2006. pp. 512–533.
Kazemi, Asma, et al. “Effect of calorie restriction or protein intake on circulating levels of insulin like growth factor I in humans: a systematic review and meta-analysis.” Clinical Nutrition 39.6 (2020): 1705-1716.
Gerontology. 2012;58(4):337-43. doi: 10.1159/000335166. Epub 2012 Jan 18.
Healthy aging: is smaller better? – a mini-review. Bartke A.
Vitale, Giovanni, et al. “Role of IGF-1 system in the modulation of longevity: controversies and new insights from a centenarians’ perspective.” Frontiers in endocrinology (2019): 27.
Grimberg A. (2003). Mechanisms by which IGF-I may promote cancer. Cancer biology & therapy, 2(6), 630–635.
Teng, H., Deng, H., Wu, Y., Zhang, C., Ai, C., Cao, H., Xiao, J. and Chen, L., 2022. Effects of Rhodiola rosea and its major compounds on insulin resistance in Caenorhabditis elegans. Journal of Future Foods, 2(4), pp.365-371.
McCormack, D., & McFadden, D. (2013). A review of pterostilbene antioxidant activity and disease modification. Oxidative medicine and cellular longevity, 2013, 575482. https://doi.org/10.1155/2013/575482
Kubo, C., Ogawa, M., Uehara, N., & Katakura, Y. (2020). Fisetin Promotes Hair Growth by Augmenting TERT Expression. Frontiers in cell and developmental biology, 8, 566617. https://doi.org/10.3389/fcell.2020.566617
Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals (Basel, Switzerland), 15(12), 1528. https://doi.org/10.3390/ph15121528
Sakai, K., & Clemmons, D. R. (2003). Glucosamine induces resistance to insulin-like growth factor I (IGF-I) and insulin in Hep G2 cell cultures: biological significance of IGF-I/insulin hybrid receptors. Endocrinology, 144(6), 2388–2395. https://doi.org/10.1210/en.2002-221133
Reynolds, J., 2022. Vitamin C Reduces IGF-1 and VEGF Signaling in Retinal Endothelial Cells.
Xu, T., Tao, M., Li, R., Xu, X., Pan, S., & Wu, T. (2022). Longevity-promoting properties of ginger extract in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway. Food & function, 13(19), 9893–9903. https://doi.org/10.1039/d2fo01602h
References – mTOR
Harrison, David E., et al. “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.” nature 460.7253 (2009): 392-395.
Ye, Lan, et al. “Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance.” (2013).
Bjedov, Ivana, et al. “Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.” Cell metabolism 11.1 (2010): 35-46.
Naghshi, Sina, et al. “Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies.” bmj 370 (2020).
Richardson, Nicole E., et al. “Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice.” Nature Aging 1.1 (2021): 73-86.
Mannick, Joan B., et al. “Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: Phase 2b and phase 3 randomised trials.” The Lancet Healthy Longevity 2.5 (2021): e250-e262.
Papadopoli, David, et al. “mTOR as a central regulator of lifespan and aging.” F1000Research 8 (2019).
Green, Cara L., Dudley W. Lamming, and Luigi Fontana. “Molecular mechanisms of dietary restriction promoting health and longevity.” Nature Reviews Molecular Cell Biology 23.1 (2022): 56-73.
Zhou, Hongyu, Yan Luo, and Shile Huang. “Updates of mTOR inhibitors.” Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 10.7 (2010): 571-581.
Liu, Z., Li, X., Simoneau, A. R., Jafari, M., & Zi, X. (2012). Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy. Molecular carcinogenesis, 51(3), 257–267. https://doi.org/10.1002/mc.20780
Su, Y., Wang, T., Wu, N., Li, D., Fan, X., Xu, Z., Mishra, S. K., & Yang, M. (2019). Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK. Aging, 11(12), 4183–4197. https://doi.org/10.18632/aging.102045
Qin, S., Wang, G., Chen, L., Geng, H., Zheng, Y., Xia, C., Wu, S., Yao, J., & Deng, L. (2023). Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression. PLoS genetics, 19(2), e1010629. https://doi.org/10.1371/journal.pgen.1010629
Hung, J. Y., Hsu, Y. L., Li, C. T., Ko, Y. C., Ni, W. C., Huang, M. S., & Kuo, P. L. (2009). 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. Journal of agricultural and food chemistry, 57(20), 9809–9816. https://doi.org/10.1021/jf902315e
References – H2S and ATF4
ATF4 activity: a common feature shared by many kinds of slow-aging mice.
Li W, Li X, Miller RA.
Aging Cell. 2014 Dec;13(6):1012-8. doi: 10.1111/acel.12264.
Hine, Christopher, et al. “Hypothalamic-pituitary axis regulates hydrogen sulfide production.” Cell metabolism 25.6 (2017): 1320-1333.
Hine, Christopher, et al. “Endogenous hydrogen sulfide production is essential for dietary restriction benefits.” Cell 160.1-2 (2015): 132-144.
Rose, Peter, et al. “Diet and hydrogen sulfide production in mammals.” Antioxidants & Redox Signaling 34.17 (2021): 1378-1393.
References – AMPK
“AMPK Signaling Pathway: Regulation and Downstream Effects“
Note: a good laymen friendly review because it is a video
Burkewitz, Kristopher, Yue Zhang, and William B. Mair. “AMPK at the nexus of energetics and aging.” Cell metabolism 20.1 (2014): 10-25.
Ulgherait, Matthew, et al. “AMPK modulates tissue and organismal aging in a non-cell-autonomous manner.” Cell reports 8.6 (2014): 1767-1780.
Timm, Kerstin N., and Damian J. Tyler. “The role of AMPK activation for cardioprotection in doxorubicin-induced cardiotoxicity.” Cardiovascular drugs and therapy 34.2 (2020): 255-269.
Apfeld, Javier, et al. “The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans.” Genes & development 18.24 (2004): 3004-3009.
Salminen, Antero, Kai Kaarniranta, and Anu Kauppinen. “Age-related changes in AMPK activation: role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways.” Ageing research reviews 28 (2016): 15-26.
Martin-Montalvo, Alejandro, et al. “Metformin improves healthspan and lifespan in mice.” Nature communications 4.1 (2013): 1-9.
La Spina, Martina, et al. “Multiple mechanisms converging on Transcription Factor EB activation by the natural phenol pterostilbene.” Oxidative medicine and cellular longevity 2021 (2021).
Koh, Yen-Chun, Chi-Tang Ho, and Min-Hsiung Pan. “Recent advances in health benefits of stilbenoids.” Journal of agricultural and food chemistry 69.35 (2021): 10036-10057.
Chen, Xiaoling, et al. “Dietary L-theanine supplementation improves lipid metabolism and antioxidant capacity in weaning piglets.” Animal Biotechnology (2022): 1-9.
Lin, Ling, et al. “Role of epigallocatechin gallate in glucose, lipid, and protein metabolism and L-Theanine in the metabolism-regulatory effects of epigallocatechin gallate.” Nutrients 13.11 (2021): 4120.
Deng, Bo, et al. “10-Gingerol, a natural AMPK agonist, suppresses neointimal hyperplasia and inhibits vascular smooth muscle cell proliferation.” Food & Function 13.6 (2022): 3234-3246.
Alipour, Alieh, Vafa Baradaran Rahimi, and Vahid Reza Askari. “Promising influences of gingerols against metabolic syndrome: A mechanistic review.” BioFactors.
Salminen, Antero, Anu Kauppinen, and Kai Kaarniranta. “FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process.” Journal of molecular medicine 95.2 (2017): 123-131.
Campbell, Jared M., et al. “Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.” Ageing Research Reviews 40 (2017): 31-44.
