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Enzyme-treated Asparagus Stem: Triggering Heat Shock Protein for Stress, Sleep & More

Asparagus Asparagus
Longevity By Nature

Chances are, you’ve never heard of heat shock proteins (HSPs). Nevertheless, these natural biochemicals produced by the body play a vital role in stress protection and longevity. This article will discuss heat shock proteins, and the role that ETAS (enzyme-treated asparagus stem), a special enzyme-treated asparagus stem extract, has in triggering their release of the heat shock protein HSP70, and the resulting beneficial effects—including improvements in stress parameters, sleep, mood, energy and other beneficial effects.


HSPs, a group of proteins that exist in virtually all living organisms, are an important part of the cell’s machinery to help to protect cells from stress, as well as being necessary for protein folding.*1,2 HSPs help protect and repair the body’s cellular proteins from heat damage that would otherwise deform and denature these proteins, rendering them nonfunctional. It is thought that HSPs are the reason that thermal and spa treatments (a form of heat stress) stimulate anti-stress and anti-aging effects. In fact, HSPs are stimulated by exercise and calorie restriction, and have been shown to have life-extending effects in animal studies.3,4 In addition, the production of HSPs is increased in the presence of heavy metals such as arsenic, cadmium and mercury, presumably to help protect cells from damage.5


Some HSPs, such as HSP70, not only protect the body from the damaging effects of stress, but also directly protect cells against damage that would otherwise lead to apoptosis, a type of early cell death. HSP70 also has anti-inflammatory and antioxidant activity, and its product-ion is stimulated by several stresses such as heat, starvation, alcohol intake, and ultraviolet radiation.6-8 However, HSP70 decreases with age, which may be related to low-grade inflammation found in the aging process.9 This decrease contributes to the development of protein-aggregation diseases, in turn leading to a reduction in cellular vigor and a decrease in lifespan.10 That’s where ETAS extract can help.

ETAS Extract

Although asparagus is commonly eaten as a nutritious vegetable, it is the tender buds and the upper part of the stem that are typically used. The main part of the stem is tough, and usually discarded. However, the “waste” part of the stems contains novel compounds called hydroxymethylfurfural derivatives, which are capable of inducing HSP70.11 In fact, in a human study,12 150 mg of ETAS daily resulted in 29.4 percent increase in HSP70. When treated with enzymes, and extracted to produce ETAS, research has demonstrated that this nutraceutical offers some significant health benefits, as discussed below.


Two human intervention trials with ETAS were conducted in healthy adult male volunteers. Study 1,13 a randomized, double-blind, placebo-controlled study, assessed the effects of 150 mg/day ETAS on the autonomic nervous system (ANS), including standard deviation of the normal and normal interval (SDNN) that represent the ANS activity, physical stress, mental stress, and overall condition in 20 healthy subjects. Results were that supplementation with ETAS was associated with improvement in all autonomic nervous condition parameters (ranging between p < 0.05 and p < 0.01). Conversely, measurements of ANS balance, SDNN, physical stress and overall evaluation were significantly decreased and worsening in the placebo group.

Study 2,14 also a randomized, double-blind, placebo-controlled, crossover trial, investigated the influence of 300 mg/day ETAS on stress-related hormones and sleep (the sleep results of this study will be in the “Sleep” section of this article) on 18 healthy adult men concerned about sleep. The results were that, after seven days, no remarkable alterations in serum and salivary cortisol were noted following ETAS intake, and salivary chromogranin A was significantly reduced (p < 0.01). By contrast, serum and salivary cortisol were significantly increased in comparison with baseline (p < 0.05 and p < 0.01, respectively) in the placebo group, with no differences in salivary chromogranin A.


Regarding the aforementioned study 2,15 ETAS intake was significantly associated with reduced actual sleep time (i.e. needing less sleep) among those with sleep efficiency over 90 percent (i.e. getting really good sleep), compared with the placebo group (p < 0.05), and showed a tendency to improve the sleep time of the subjects with less than 90 percent sleep efficiency. In addition, the AIS score for awakening earlier than desired was significantly improved among those taking ETAS compared with placebo (p < 0.05); and the OSA-MA score reported less frequency of dreaming and nightmares when subjects consumed ETAS (p < 0.05). ETAS also significantly contributed to increased appetite by VAS score (p < 0.01).

Mood & Energy

In a randomized, double-blind, placebo-controlled crossover trial,16 25 healthy volunteers were given 150 mg/day of ETAS or a placebo for 28 days with a 14-day washout period. A questionnaire survey of the subject’s energy or fatigue condition was used and utilized mental arithmetic to cause psychological stress. The autonomic-nervous functions were measured by the heart rate variability analyses. After the mental arithmetic test, different stress parameters were analyzed, including serum catecholamine hormones, sIgA (a salivary immune factor that is reduced from stress), and cortisol. The results of ETAS intake for 28 days showed an increase in the levels of sIgA, reduced feelings of tiredness in daily living, and an improvement in the dysphoric condition (e.g. unhappiness).

Other Beneficial Effects

In addition to the benefits for stress, sleep, mood and energy, laboratory research has demonstrated that ETAS has other beneficial effects on physiological functions. This includes anti-inflammatory activity,17 reduced cell toxicity and excess cell proliferation under normal conditions and under oxidant stress, reduced neuronal cellular stress, prevention of beta amyloid (βA)-induced cell death, reduced βA-induced DNA damage as well as generation of reactive oxidized species, and protecting brain cells from damage by enhancing cell viability in the presence of βA.18


Heat shock proteins are produced by the body and play a vital role in stress protection and longevity. HSP70 is an important heat shock protein that decreases with age. ETAS is an enzyme-treated asparagus stem extract shown to increase HSP70 in the body. In human research, ETAS has also been shown to improve various parameters of stress (including the reduction of key stress hormones), promote improvements in sleep, reduce tiredness and improve mood. All of these results occurred with a daily dose of 150 to 300 mg. In laboratory research, ETAS has also demonstrated anti-inflammatory effects, and protection against certain effects of beta amyloid nerve/brain cells.

*Protein folding is the physical process by which a protein chain acquires its 3-dimensional structure, usually allowing it to be biologically functional.


1 Tavaria M, Gabriele T, Kola I, Anderson RL. A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperones. 1996;1(1):23–8.

2 Morano KA. New tricks for an old dog: the evolving world of Hsp70. Ann. N. Y. Acad. Sci. October 2007;1113:1–14.

3 Iguchi M, Littmann AE, Chang SH, Wester LA, Knipper JS, Shields RK. Heat stress and cardiovascular, hormonal, and heat shock proteins in humans. J Athl Train 2012; 47(2): 184–90.

4 Calderwood SK, A. Murshid, T. Prince. The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review. Gerontology. 2009: 55(5): 550–8.

5 Ritossa F. A new puffing pattern induced by temperature shock and DNP in drosophila. Cell Mol Life Sci. 1962;18(12):571–573.

6 Doeppner TR, B. Kaltwasser, J. Fengyan, D.M. Hermann, M. Bähr. TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells. J Cereb Blood Flow Metab. 2013 Nov;33(11):1778-88.

7 Matsuda M, T. Hoshino, N. Yamakawa, K. Tahara, H. Adachi, G. Sobue, D. Maji, H. Ihn, T. Mizushima. Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice. J Invest Dermatol. 2013; 133(4): 919–28.

8 Akagi R, M. Ohno, K. Matsubara, M. Fujimoto, A. Nakai, S. Inouye. Glutamine protects intestinal barrier function of colon epithelial cells from ethanol by modulating Hsp70 expression. Pharmacology. 2013; 91(1–2): 104–11.

9 Njemini R, Bautmans I, Onyema OO, Van Puyvelde K, Demanet C, Mets T. Circulating heat shock protein 70 in health, aging and disease. BMC Immunol. 2011 Mar 28;12:24.

10 Calderwood SK, A. Murshid, T. Prince. The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review. Gerontology. 2009: 55(5): 550–8.

11 Ito T. Isolation, Structural Elucidation, and Biological Evaluation of 5-Hydroxymethyl-2-furfural Derivative, Asfural, from Enzyme-Treated Asparagus Extract. J Agric Food Chem. 2013; 61: 9155−9159.

12 Ito T, Maeda T, Goto K, Miura T, Wakame K, Nishioka H, Sato A. Enzyme-treated asparagus extract promotes expression of heat shock protein and exerts antistress effects. J Food Sci. 2014 Mar;79(3):H413-9.

13 Ito T, Goto K, Takanari J, Miura T, Wakame K, Nishioka H, Tanaka A, Nishihira J. Effects of enzyme-treated asparagus extract on heat shock protein 70, stress indices, and sleep in healthy adult men. J Nutr Sci Vitaminol. 2014;60(4):283-90.

14 Ito T, Goto K, Takanari J, Miura T, Wakame K, Nishioka H, Tanaka A, Nishihira J. Effects of enzyme-treated asparagus extract on heat shock protein 70, stress indices, and sleep in healthy adult men. J Nutr Sci Vitaminol. 2014;60(4):283-90.

15 Ito T, Goto K, Takanari J, Miura T, Wakame K, Nishioka H, Tanaka A, Nishihira J. Effects of enzyme-treated asparagus extract on heat shock protein 70, stress indices, and sleep in healthy adult men. J Nutr Sci Vitaminol. 2014;60(4):283-90.

16 Waki H, Miyazaki S, Miura T, Uebaba K, Hisajima T. Effect of Enzyme-Treated Asparagus (ETAS) on the Stress Response Substance in a Clinical Trial. Clinical Nutrition. 2013;32: S233–S234.

17 Nishizawa M, Kano M, Okuyama T, Okumura T, Ikeya Y. Anti-inflammatory effects of enzyme-treated asparagus extract and its constituents in hepatocytes. FFHD. 2016;6(2):91-109.

18 Ogasawara J. Inhibitory Effect of ETAS against Amyloid Beta-induced Cellular Disorder in PC12 Cells. Amino Up Chemical Co. Ltd., Sapporo, Japan, no date.


Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at gbruno@hchs.edu.