Targeting aging-associated pathways: a novel therapeutic approach for cancer

*Article not assigned to an issue yet


Review Articles | Published:

Print ISSN : 0970-4078.
Online ISSN : 2229-4473.
Pub Email:
Doi: 10.1007/s42535-023-00598-1
First Page: 0
Last Page: 0
Views: 360

Keywords: Aging, Intracellular stress, Anti-cancer, Natural compounds, Proteostasis


Aging has been found to be associated with the onset and progression of multiple diseases. Anti-aging approaches using natural compounds have been an area of active research, since they focus on restoring the lost cellular homeostasis and regeneration. But diseases like cancer require the exact opposite effect specifically in the affected cells, i.e. the induction of cell death by apoptosis due to induced loss of homeostasis (pro-aging). The present study critically reviews aging related therapeutic approaches in cancer. Interestingly, it has been found that anti-aging approaches can bring therapeutic effects in the early stages of cancer but in the advanced stages of cancer only pro-aging approaches have been observed to deliver therapeutic effects by inducing cellular damage followed by apoptosis in cancer cells. We have extensively reviewed many such pro-aging approaches, including stimulation of mitochondrial dysfunction, oxidative stress and endoplasmic reticulum (ER) stress and impairment of ubiquitin–proteasome system (UPS) and autophagy, that have been shown to induce cell death by apoptosis in different cancer cells and thereby inhibit tumor proliferation. Natural compounds that have been found to stimulate the aforementioned pro-aging pathways may hold a key towards the use of novel therapeutics in combinatorial cancer therapeutics. Many such natural compounds have been reviewed in this study. Some natural compounds including polyphyllins and myricetin have been observed to stimulate multiple pro-aging pathways simultaneously in different cancer cells, thereby producing more robust results. Thus, the present study sheds light on the uncharted potential of natural compounds and aging-related therapeutic approaches in cancer.

Graphical abstract

Aging, Intracellular stress, Anti-cancer, Natural compounds, Proteostasis

*Get Access

(*Only SPR Members can get full access. Click Here to Apply and get access)



Ahmad B, Gamallat Y, Khan MF, Din SR, Israr M et al (2021) Natural polyphyllins (I, II, D, VI, VII) reverses cancer through apoptosis, autophagy, mitophagy, inflammation, and necroptosis. Onco Targets Ther 14:1821–1841

Ahn J, Kim H, Yang KM (2020) ω-Hydroxyundec-9-enoic acid induction of breast cancer cells apoptosis through generation of mitochondrial ROS and phosphorylation of AMPK. Arch Pharmacal Res 43(7):735–743

Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK et al (2021) Autophagy in healthy aging and disease. Nat Aging 1(8):634–650

Ashrafizadeh M, Bakhoda MR, Bahmanpour Z, Ilkhani K, Zarrabi A et al (2020) Apigenin as tumor suppressor in cancers: biotherapeutic activity, nanodelivery, and mechanisms with emphasis on pancreatic cancer. Front Chem.

Azab AK, Muz B, Ghazarian R, Ou M, Luderer M et al (2016) Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Des Dev Ther 10:217–226

Bhattarai KR, Chaudhary M, Kim H-R, Chae H-J (2020) Endoplasmic reticulum (ER) stress response failure in diseases. Trends Cell Biol 30(9):672–675

Cai SJ, Liu Y, Han S, Yang C (2019) Brusatol, an NRF2 inhibitor for future cancer therapeutic. Cell Biosci 9(1):45

Chaurasia M, Gupta S, Das A, Dwarakanath BS, Simonsen A et al (2019) Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy. Autophagy 15(8):1391–1406

Chavez-Dominguez R, Perez-Medina M, Lopez-Gonzalez JS, Galicia-Velasco M, Aguilar-Cazares D (2020) The double-edge sword of autophagy in cancer: from tumor suppression to pro-tumor activity. Front Oncol.

Chen M, Xie S (2018) Therapeutic targeting of cellular stress responses in cancer. Thorac Cancer 9(12):1575–1582

da Silva PFL, Schumacher B (2021) Principles of the molecular and cellular mechanisms of aging. J Invest Dermatol 141(4S):951–960

Darrigrand R, Pierson A, Rouillon M, Renko D, Boulpicante M et al (2021) Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens. Commun Biol 4(1):269

Desideri E, Ciccarone F, Ciriolo MR (2019) Targeting glutathione metabolism: partner in crime in anticancer therapy. Nutrients 11(8):1926

Ebstein F, Poli Harlowe MC, Studencka-Turski M, Krüger E (2019) Contribution of the unfolded protein response (UPR) to the pathogenesis of proteasome-associated autoinflammatory syndromes (PRAAS). Front Immunol.

Franceschi C, Garagnani P, Morsiani C, Conte M, Santoro A et al (2018) The continuum of aging and age-related diseases: common mechanisms but different rates. Front Med.

Fu X, Cui J, Meng X, Jiang P, Zheng Q et al (2021) Endoplasmic reticulum stress, cell death and tumor: association between endoplasmic reticulum stress and the apoptosis pathway in tumors (review). Oncol Rep 45(3):801–808

Guo Z, Guozhang H, Wang H, Li Z, Liu N (2019) Ampelopsin inhibits human glioma through inducing apoptosis and autophagy dependent on ROS generation and JNK pathway. Biomed Pharmacother 116:108524

Huang M, Lu J-J, Ding J (2021) Natural products in cancer therapy: past, present and future. Nat Prod Bioprospect 11(1):5–13

Imran M, Rauf A, Abu-Izneid T, Nadeem M, Shariati MA et al (2019) Luteolin, a flavonoid, as an anticancer agent: a review. Biomed Pharmacother 112:108612

Jayaweera SPE, WanigasingheKanakanamge SP, Rajalingam D, Silva GN (2021) Carfilzomib: a promising proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Front Oncol.

Jia P, Dai C, Cao P, Sun D, Ouyang R et al (2020) The role of reactive oxygen species in tumor treatment. RSC Adv 10(13):7740–7750

Kara M, Oztas E (2020) Endoplasmic reticulum stress-mediated cell death programmed cell death. IntechOpen, USA

Khan AQ, Rashid K, AlAmodi AA, Agha MV, Akhtar S et al (2021) Reactive oxygen species (ROS) in cancer pathogenesis and therapy: an update on the role of ROS in anticancer action of benzophenanthridine alkaloids. Biomed Pharmacother 143:112142

Kim SJ, Kim HS, Seo YR (2019) Understanding of ROS-inducing strategy in anticancer therapy. Oxid Med Cell Longev 2019:1–12

Kung F-P, Lim Y-P, Chao W-Y, Zhang Y-S, Yu H-I et al (2021) Piperlongumine, a potent anticancer phytotherapeutic, induces cell cycle arrest and apoptosis in vitro and in vivo through the ROS/Akt pathway in human thyroid cancer cells. Cancers 13(17):4266

Li Q, Wang Z, Xie Y, Hu H (2020) Antitumor activity and mechanism of costunolide and dehydrocostus lactone: two natural sesquiterpene lactones from the Asteraceae family. Biomed Pharmacother 125:109955

Liu Y, Shi Y (2020) Mitochondria as a target in cancer treatment. MedComm 1(2):129–139

Liu T, Zhang J, Li K, Deng L, Wang H (2020) Combination of an autophagy inducer and an autophagy inhibitor: a smarter strategy emerging in cancer therapy. Front Pharmacol.

Min F, Liu X, Li Y, Dong M, Qu Y et al (2021) Carnosic acid suppresses the development of oral squamous cell carcinoma via mitochondrial-mediated apoptosis. Front Oncol.

Moghadam ZM, Henneke P, Kolter J (2021) From flies to men: ROS and the NADPH oxidase in phagocytes. Front Cell Dev Biol 9:618

Mulcahy Levy JM, Thorburn A (2020) Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27(3):843–857

Ong CP, Lee WL, Tang YQ, Yap WH (2019) Honokiol: a review of its anticancer potential and mechanisms. Cancers 12(1):48

Park JE, Miller Z, Jun Y, Lee W, Kim KB (2018) Next-generation proteasome inhibitors for cancer therapy. Transl Res 198:1–16

Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ (2019) Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med 51(12):1–13

Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P et al (2020) ROS in cancer therapy: the bright side of the moon. Exp Mol Med 52(2):192–203

Ren H, Zhai W, Lu X, Wang G (2021) The cross-links of endoplasmic reticulum stress, autophagy, and neurodegeneration in Parkinson’s disease. Front Aging Neurosci.

Sarvizadeh M, Hasanpour O, NaderiGhale-Noie Z, Mollazadeh S, Rezaei M et al (2021) Allicin and digestive system cancers: from chemical structure to its therapeutic opportunities. Front Oncol.

Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L et al (2020) Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Front Physiol.

Sharifi-Rad J, Herrera-Bravo J, Salazar LA, Shaheen S, AbdulmajidAyatollahi S et al (2021) The therapeutic potential of Wogonin observed in preclinical studies. Evid Based Complement Alternat Med 2021:9935451

Song X, Tan L, Wang M, Ren C, Guo C et al (2021) Myricetin: a review of the most recent research. Biomed Pharmacother 134:111017

Talebi M, Talebi M, Farkhondeh T, Simal-Gandara J, Kopustinskiene DM et al (2021) Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin. Cancer Cell Int 21(1):214

Tian X, Zhang S, Zhou L, Seyhan AA, Hernandez Borrero L et al (2021) Targeting the integrated stress response in cancer therapy. Front Pharmacol.

Verma K, Verma M, Chaphalkar A, Chakraborty K (2021) Recent advances in understanding the role of proteostasis. Fac Rev.

Wu M-Y, Wang S-F, Cai C-Z, Tan J-Q, Li M et al (2017) Natural autophagy blockers, dauricine (DAC) and daurisoline (DAS), sensitize cancer cells to camptothecin-induced toxicity. Oncotarget 8(44):77673–77684

Wu S, Lu H, Bai Y (2019) Nrf2 in cancers: a double-edged sword. Cancer Med 8(5):2252–2267

Yang Y, Tian Z, Guo R, Ren F (2020) Nrf2 inhibitor, brusatol in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive cancers by inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 pathways. Oxid Med Cell Longev 2020:1–14

Yokoyama NN, Denmon AP, Uchio EM, Jordan M, Mercola D et al (2015) When anti-aging studies meet cancer chemoprevention: can anti-aging agent kill two birds with one blow? Curr Pharmacol Rep 1(6):420–433

Zhou Y, Shu F, Liang X, Chang H, Shi L et al (2014) Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway. PLoS ONE 9(2):e89021

Zhou Li, Gao W, Wang K, Huang Z, Zhang L et al (2019a) Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy. FASEB J 33(4):5520–5534

Zhou L, Tan J, Cao R, Xu J, Chen X et al (2019b) ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis. Cell Death Dis 10(9):662

Zhu M, Zhang P, Jiang M, Yu S, Wang L (2020) Myricetin induces apoptosis and autophagy by inhibiting PI3K/Akt/mTOR signalling in human colon cancer cells. BMC Complement Med Ther 20(1):209



The present study has been carried out in the Department of Biotechnology, Delhi Technological University, following all ethical principles of the university.

Author Information

Sharma Yuvraj
Department of Biotechnology, Delhi Technological University, Delhi, India

Das Asmita
Department of Biotechnology, Delhi Technological University, Delhi, India