Talk:Senolytic

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Primary sources

Hyperforin I appreciate you working to expand the article but please stop building it with primary sources; please use reviews. The goal of Wikipedia is to transmit "accepted knowledge" and original research papers published in the biomedical literature are not intended to communicate accepted knowledge - they are intended to communicate experimental results to other scientists. Thanks. Jytdog (talk) 23:29, 6 February 2016 (UTC)[reply]

I would certainly prefer them myself when available. In the case of AP20187, unfortunately I couldn't find one; I suppose the agent is too new in this context. I also want to note that Dmitry Dzhagarov indirectly baited me into writing about AP20187 by adding it to the Further reading section. --Hyperforin 23:41, 6 February 2016 (UTC) — Preceding unsigned comment added by Hyperforin (talk • contribs)

Please don't allow yourself to be baited, and in my view if something isn't important enough to have been discussed in a review it doesn't belong in WP - not even in "Further reading" (think of how insane those sections would become if we listed every study that has been published there! And if list one, how can we say no to any others? There would be no end to it.) Anyway thanks for being open to what I said and for working to improve WP! Jytdog (talk) 23:50, 6 February 2016 (UTC)[reply]

Per your feedback, and for what it's worth, a secondary reference has now been added to substantiate the claims for AP20187. --Hyperforin (talk) 00:32, 8 February 2016 (UTC)[reply]

AP20187

Please do not perform editing if do not understand the material. AP20187 is not senolytic at all. AP20187 is a synthetic drug, capable of inducing dimerization of the engineered construct caspase 8 fusion protein, thereby inducing apoptosis in Transgenic animals^[1]. I took this article^[2] for a general overview to the Further reading section.

References

^ Pajvani, U. B., Trujillo, M. E., Combs, T. P., Iyengar, P., Jelicks, L., Roth, K. A., ... & Scherer, P. E. (2005). Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nature medicine, 11(7), 797-803
^ Kirkland, J. L., Tchkonia, T., van Deursen, J. M., & Baker, D. J. (2012). Transgenic animals capable of being induced to delete senescent cells U.S. Patent Application No. 14/125,841.

- Dmitry Dzhagarov (talk) 14:47, 10 February 2016 (UTC)[reply]

In view of your comment, the section on AP20187 has been moved to a new location where any confusion about AP20187 not being senolytic should be further minimized. --Hyperforin (talk) 22:53, 15 February 2016 (UTC)[reply]

ABT-737

What is the rationale for including this content?

Reut Yosef et al & Valery Krizhanovsky^[1] show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14ARF.

References

^ Reut Yosef, Noam Pilpel, Ronit Tokarsky-Amiel, Anat Biran, Yossi Ovadya, Snir Cohen, Ezra Vadai, Liat Dassa, Elisheva Shahar, Reba Condiotti, Ittai Ben-Porath & Valery Krizhanovsky (2016). Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nature Communications 7, Article number: 11190 doi:10.1038/ncomms11190

There is nothing use-able here, including the formatting. Please explain User:Voodoogoogoo 10:13, 11 April 2016 (UTC)[reply]

There are plenty of secondary sources that exist for ABT-737, but none that I could find to verify it as a senolytic. --Hyperforin (talk) 03:48, 12 April 2016 (UTC)[reply]

Urolithin A

Urolithin A is a mitophagy inducer.^[1] It has the hallmarks of a possible health-promoting mitochondrial senolytic, especially in seniors. It is produced by specific gastrointestinal microbiota from ellagitannins and ellagic acid, both of which are found mainly in pomegranate. There are many pomegranate ellagitannins. --Hyperforin (talk) 04:46, 14 July 2016 (UTC)[reply]

Basic research

Moved from the main article as WP:PRIMARY and WP:NOTJOURNAL. --Zefr (talk) 00:43, 12 July 2017 (UTC)[reply]

Studies in animals and cells

The senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging.^[2] As such, chronic accumulation of senescent cells can lead to cancer in addition to aging.^[3]

Senescent cells are similar to cancer cells in that they have increased expression of so-called pro-survival networks that help them resist apoptosis (programmed cell death).^[4]

The elimination of p16-expressing senescent cells can impair wound healing.^[3]^[5] This is due to a positive role of senescent cells during tissue repair.^[5] The presence of senescent cells also restrains fibrosis.^[5] Their absence significantly retards the kinetics of wound closure.^[5]

Senolytics induce apoptosis preferentially in senescent cells.^[6] Although apoptosis is a mechanism of anti-cancer defense, it can also drive tumor formation.^[7] It can promote proliferation critically needed to compensate for cell loss and to restore tissue homeostasis.^[7] Apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage.^[7] Tumorigenesis is initiated by repeated cell attrition and repopulation, as demonstrated in therapy-induced secondary malignancies and myelodysplastic syndromes.^[7]

The combination of dasatinib and quercetin, the first senolytic drugs discovered, reduced senescent cell burden in multiple tissues of old mice and in the legs of young mice after senescence had been induced by radiation. The senolytic drugs improved cardiovascular function in old mice as well as mice with atherosclerosis,^[8] restored leg function in the younger mice that had received leg irradiation sufficient to impair walking, and enhanced healthspan in mice with an "accelerated aging" condition. In these mice, the combination of dasatinib and quercetin delayed neurological dysfunction, bone loss, and dysfunction of intervertebral discs of the backbone.^[4]

An engineered suicide gene was used in transgenic mice to delete senescent cells.^[9] This approach demonstrates that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.^[10] It provided the first direct evidence that senescent cells can, at least in a premature aging mouse model, drive degenerative age-related pathology, and that clearance of such cells can delay or arrest senescence.^[11]

AP20187 was used to activate an engineered suicide gene under the promoter for p16 in transgenic mice. Cells expressing p16 are predominantly senescent, and administration of AP20187 led to selective apoptosis of these cells. AP20187 was used to restore fat tissue and stem cell function in older naturally-aged mice.^[12] AP20187 was used similarly in a later study to extend the median lifespan of mice.^[13] In these mice, the clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects.^[13] Furthermore, late-life clearance of these cells attenuated progression of cancers and of established age-related disorders.^[10]

References

^ Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J (2016). "Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents" (PDF). Nature Medicine. doi:10.1038/nm.4132. PMID 27400265. Retrieved 2016-07-14.
^ Loaiza N, Demaria M (2016). "Cellular senescence and tumor promotion: Is aging the key?". Biochimica et Biophysica Acta. 1865: 155–67. doi:10.1016/j.bbcan.2016.01.007. PMID 26845683. Retrieved 2016-02-07. We also discuss how the senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. We argue that three age-related phenomena-senescence-associated secretory phenotype (SASP) dysregulation, decline in the immune system function and genomic instability-could contribute, independently or synergistically, to deteriorate the efficacy of the senescence response in stopping cancer. As a consequence, senescent cells could be considered premalignant cells, and targeting senescent cells could be a preventive and therapeutic strategy against cancer.
^ ^a ^b Lujambio, A (2016). "To clear, or not to clear (senescent cells)? That is the question". Inside the Cell. 1: 87–95. doi:10.1002/icl3.1046. Retrieved 2016-02-28. • chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging.
• the genetic elimination of p16-expressing senescent cells was recently shown to impair wound healing
^ ^a ^b Cite error: The named reference pmid25754370 was invoked but never defined (see the help page).
^ ^a ^b ^c ^d Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014). "An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA". Developmental Cell. 31 (6): 722–33. doi:10.1016/j.devcel.2014.11.012. PMC 4349629. PMID 25499914. Retrieved 2016-03-19.
• Thus, elimination of senescent cells by GCV depleted wound sites of myofibroblasts, consistent with the slower wound healing shown by GCV-treated p16-3MR mice.
• These data support a positive role for senescent cells during tissue repair and help to explain why the SASP evolved.
• In agreement with previous findings (Jun and Lau, 2010; Krizhanovsky et al., 2008), we also found that the presence of senescent cells restrains fibrosis.
• These data indicate that senescent cells facilitate cutaneous wound repair and that their absence significantly retards the kinetics of wound closure.
^ Cite error: The named reference pmid26711051 was invoked but never defined (see the help page).
^ ^a ^b ^c ^d Labi V, Erlacher M (2015). "How cell death shapes cancer". Cell Death & Disease. 6: e1675. doi:10.1038/cddis.2015.20. PMC 4385913. PMID 25741600. Retrieved 2015-12-27.
^ Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD (2016). "Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice". Aging Cell. doi:10.1111/acel.12458. PMID 26864908. Retrieved 2016-02-15. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.
^ US Patent Application No. 20150296755 James L. Kirkland, Tamar Tchkonia, Jan M.A. van Deursen, Darren J. Baker (2015) Transgenic animals capable of being induced to delete senescent cells
^ ^a ^b Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011). "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders". Nature. 479 (7372): 232–6. doi:10.1038/nature10600. PMC 3468323. PMID 22048312. Retrieved 2016-02-06. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
^ Cite error: The named reference pmid23140366 was invoked but never defined (see the help page).
^ Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL (2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4: e12997. doi:10.7554/eLife.12997. PMC 4758946. PMID 26687007. Retrieved 2016-02-10.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, A Saltness R, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016). "Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan". Nature. 530: 184–9. doi:10.1038/nature16932. PMC 4845101. PMID 26840489. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively.

Revert 18/7/12

My edit was reverted today. The primary focus of the edit was to supply an oft-wished for secondary source for the article. What's up? Lfstevens (talk) 03:58, 13 July 2018 (UTC)[reply]

This reverted edit not only misleads the reader to believe there are conclusive results about senolytics, but relies only on preliminary lab studies, WP:PRIMARY. In writing for an encyclopedia, we rely on systematic reviews of completed, high-quality clinical trials, for which there are none in the senolytics field. The section you added was overstated and undersourced. Here's a tutorial for further explanation about WP:MEDRS source quality. --Zefr (talk) 13:32, 13 July 2018 (UTC)[reply]

Do you realise that there won't be "...systematic reviews of completed, high-quality clinical trials..."

For senolytics to get that, aging would have to be classed as a disease, which it isn't. 80.110.41.148 (talk) 09:33, 12 February 2024 (UTC)[reply]

Converted list to a table; it is missing info from reviews and should be improved

I converted the list to a table to inform about the type of tests done so far as WP:MEDANIMAL says:

Where in vitro and animal-model data are cited on Wikipedia, it should be clear to the reader that the data are pre-clinical, and the article text should avoid stating or implying that reported findings hold true in humans. The level of support for a hypothesis should be evident to a reader.

With this, the list should now be compliant or more compliant with the content policies.

There are many ways the table could (and should) be improved (especially over time):

You could add a "Type" column if there are categories of senolytics and a "Target" column, especially as the list currently intermingles targets and medications/specific treatment options

We could also have separate tables for Senolytic candidates, Senolytic target candidates, and Discarded/discontinued senolytic candidates

It does not inform about how many studies reported such effects per type or the effect sizes (per type) or the already known current problems or the age of the mice or the types of human cells it was tested with in vitro

For example, this review has "As summarized above, only a small number of natural compounds were evidenced to be effective senolytic agents in vitro. However, two of them have been demonstrated to beneficial to health in animal models, that is, fisetin and quercetin; the rest are yet to be determined" and "beneficial to health in animal model" could be built into the "Mice" column.

Moreover, I didn't add a "Primates" column because it doesn't look like any were tested in primates other than humans but such a column could be added if there any of candidates were tested with such.

Some of the reviews, like this one under "Table 1", this under "Table 1" and this also under "Table 1", list more candidates.

We should probably add/remove/decide about which to include here – such as which are notable/viable. So far I didn't add any further one(s) and if I'll do later, I'd like to know other editors' take on this first.

For example, one approach would be to just list all of them, even discontinued and nonviable ones, but add columns (which) that allow readers to easily filter them / view that info (like a "Discontinued" column and so on).

Also currently not included are many of the candidates in clinical trials listed in this review here in "Table 3" (such as "UBX1325").

There may be studies that are not yet included here about other tests/trials, so far I only added info about the type of testing in the current refs (I may improve upon this later but it may take a while so please do add missing info if you know of or find such)

For these reasons ^ and other ones the table isn't perfect of course but I can't do everything on my own (such as only publishing edits once I went through all reviews and extracted all the due useful info in the best possible way or similar) and it would be wrong to expect all article sections to be perfect before not removing/reverting them in their entirety (Wikipedia is iterative and things get improved/edit rather than being published in the best possible way with one edit). It's an improvement over the prior content, unlike the prior content is (better) compliant with WP:MEDANIMAL, unlike the prior content now uses multiple WP:MEDRS reviews, and should be improved further.

I also added short info on intermittent administration and Senomorphics. Prototyperspective (talk) 13:32, 27 January 2022 (UTC)[reply]

@Prototyperspective This table made the things a lot clearer and hopefully will contribute to make future edits (and reverts) a lot more transparent too and is also a reminder that we should always consider to improve/correct before reverting/deleting, kudos for you Dabed (talk) 15:28, 31 January 2022 (UTC)[reply]

[1] Pajvani, U. B., Trujillo, M. E., Combs, T. P., Iyengar, P., Jelicks, L., Roth, K. A., ... & Scherer, P. E. (2005). Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nature medicine, 11(7), 797-803

[2] Kirkland, J. L., Tchkonia, T., van Deursen, J. M., & Baker, D. J. (2012). Transgenic animals capable of being induced to delete senescent cells U.S. Patent Application No. 14/125,841.

[3] Reut Yosef, Noam Pilpel, Ronit Tokarsky-Amiel, Anat Biran, Yossi Ovadya, Snir Cohen, Ezra Vadai, Liat Dassa, Elisheva Shahar, Reba Condiotti, Ittai Ben-Porath & Valery Krizhanovsky (2016). Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nature Communications 7, Article number: 11190 doi:10.1038/ncomms11190

[pmid27400265-4] Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Félix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, Aebischer P, Sandi C, Rinsch C, Auwerx J (2016). "Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents" (PDF). Nature Medicine. doi:10.1038/nm.4132. PMID 27400265. Retrieved 2016-07-14.

[pmid26845683-5] Loaiza N, Demaria M (2016). "Cellular senescence and tumor promotion: Is aging the key?". Biochimica et Biophysica Acta. 1865: 155–67. doi:10.1016/j.bbcan.2016.01.007. PMID 26845683. Retrieved 2016-02-07. We also discuss how the senescence response, initially a tumor suppressor mechanism, turns into a tumor promoter apparently as a consequence of aging. We argue that three age-related phenomena-senescence-associated secretory phenotype (SASP) dysregulation, decline in the immune system function and genomic instability-could contribute, independently or synergistically, to deteriorate the efficacy of the senescence response in stopping cancer. As a consequence, senescent cells could be considered premalignant cells, and targeting senescent cells could be a preventive and therapeutic strategy against cancer.

[icl3.1046-6] Lujambio, A (2016). "To clear, or not to clear (senescent cells)? That is the question". Inside the Cell. 1: 87–95. doi:10.1002/icl3.1046. Retrieved 2016-02-28. • chronic accumulation of senescent cells leads to more detrimental consequences, namely, cancer and aging.
• the genetic elimination of p16-expressing senescent cells was recently shown to impair wound healing

[pmid25754370-7] Cite error: The named reference pmid25754370 was invoked but never defined (see the help page).

[pmid25499914-8] Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014). "An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA". Developmental Cell. 31 (6): 722–33. doi:10.1016/j.devcel.2014.11.012. PMC 4349629. PMID 25499914. Retrieved 2016-03-19.
• Thus, elimination of senescent cells by GCV depleted wound sites of myofibroblasts, consistent with the slower wound healing shown by GCV-treated p16-3MR mice.
• These data support a positive role for senescent cells during tissue repair and help to explain why the SASP evolved.
• In agreement with previous findings (Jun and Lau, 2010; Krizhanovsky et al., 2008), we also found that the presence of senescent cells restrains fibrosis.
• These data indicate that senescent cells facilitate cutaneous wound repair and that their absence significantly retards the kinetics of wound closure.

[pmid26711051-9] Cite error: The named reference pmid26711051 was invoked but never defined (see the help page).

[pmid25741600-10] Labi V, Erlacher M (2015). "How cell death shapes cancer". Cell Death & Disease. 6: e1675. doi:10.1038/cddis.2015.20. PMC 4385913. PMID 25741600. Retrieved 2015-12-27.

[pmid26864908-11] Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD (2016). "Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice". Aging Cell. doi:10.1111/acel.12458. PMID 26864908. Retrieved 2016-02-15. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

[uspto20150296755-12] US Patent Application No. 20150296755 James L. Kirkland, Tamar Tchkonia, Jan M.A. van Deursen, Darren J. Baker (2015) Transgenic animals capable of being induced to delete senescent cells

[pmid22048312-13] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011). "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders". Nature. 479 (7372): 232–6. doi:10.1038/nature10600. PMC 3468323. PMID 22048312. Retrieved 2016-02-06. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

[pmid23140366-14] Cite error: The named reference pmid23140366 was invoked but never defined (see the help page).

[pmid26687007-15] Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, Sepe A, Johnson KO, Stout MB, Giorgadze N, Jensen MD, LeBrasseur NK, Tchkonia T, Kirkland JL (2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4: e12997. doi:10.7554/eLife.12997. PMC 4758946. PMID 26687007. Retrieved 2016-02-10.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[pmid26840489-16] Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, A Saltness R, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016). "Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan". Nature. 530: 184–9. doi:10.1038/nature16932. PMC 4845101. PMID 26840489. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively.

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