














































The Role of the Gut Microbiome in Neuromodulation Therapies as a Potential Treatment Adjunct for Multiple Sclerosis


Abstract

Berkeley
Pharma Tech
Journal of Medicine

Correspondence:
jwlarrick@gmail.com

Keywords:
Chloroquine, hydrochloroquine, 
autophagy, aging, geroprotection

Submitted: March 10, 2023 
Accepted: April 6, 2023 
Published: June 30, 2023

Full Open Access

Creative Commons Attribution 
License 4.0

Autophagy, the turnover of cellular components including organelles, 
declines with age. Thus, enhancement of this characteristic process is 
hypothesized to improve health and extend lifespan.  Two recent papers 
present data indicating that contrary to expectation, chloroquine (CQ), a 
nominal inhibitor of autophagy, extended the lifespan of middle-aged mice 
and rats by ~10%.  Details of these studies provide a cautionary tale 
regarding traditional reagents or “tool compounds” of “established” 
mechanisms often used in cellular biological research. However, these and 
earlier studies support a deeper investigation of CQ or its more commonly 
used clinical analog, hydroxychloroquine (HCQ), as potential drugs to 
increase health span and slow the aging  process.

Chloroquine defeats aging?
By: James W. Larrick, M.D. Ph.D. and Jasmine W. Larrick



 Introduction 

 1.1  Autophagy 

 Autophagy,  literally  “self-eating,"  was  �rst  described  by  Christian  De  Duve, 
 who  shared  the  1974  Nobel  prize  for  his  discovery  of  lysosomes. 
 Autophagy  is  an  evolutionarily  conserved  catabolic  process  wherein 
 lysosomes  degrade  various  cellular  components  to  maintain  cytoplasmic 
 quality  control  and  thus  cellular  homeostasis.  Several  distinct  forms  of 
 autophagy  include  macroautophagy,  microautophagy,  and 
 chaperone-mediated  autophagy  (CMA).  Dysregulation  of  this  critical 
 process  has  been  associated  with  many  pathological  processes  including 
 infectious,  metabolic,  and  neurodegenerative  disorders,  as  well  as  cancer  and 
 autoimmunity.  Reduced  autophagy  was  identi�ed  by  López-Otín  et  al. 
 (2013) as a so-called "Hallmark of aging". 

 1.2  Chloroquine 

 Native peoples of South America have long used an extract of the bark of 
 the Cinchona tree (  Cinchona officinalis  ) as a remedy  for fevers.  By the 
 1600s, this herbal medicine was being used in Europe for treatment of 
 malaria. Quinine was isolated from the bark in 1820. Seeking an alternative 
 to quinine, Bayer chemists discovered chloroquine, a synthetic analog with a 
 similar mechanism of action.  A related analogue, 3-methyl-chloroquine, 
 was utilized by the Germans in World War II. Material captured by the 
 Americans in North Africa was analyzed by the United States government, 
 resulting in corroborative studies and subsequent clinical approval in 1947 
 of chloroquine as a prophylactic treatment for malaria. While chloroquine 
 and its derivative hydroxychloroquine are widely used in rheumatology 
 (SLE, RA, etc.)  1  , chloroquine-resistant malaria has  mandated the 
 development of newer antimalarials such as pyrimethamine, artemisinin and 
 me�oquine  2  . 

 Chloroquine inhibits hemozoin formation from the heme released by 
 parasitic digestion of erythrocyte hemoglobin during Plasmodium 
 infection. The free heme then lyses membranes and leads to parasite death  3,

 4, 5  . Chloroquine passively di�uses through cell  membranes and into 

 Berkeley Pharma Tech Journal of Medicine |  2 



 endosomes, lysosomes, and Golgi vesicles which become protonated, 
 trapping the chloroquine in the organelles and raising the surrounding pH. 
 The raised pH in the endosomal compartments (a so-called lysosomotropic 
 e�ect), inhibits viral infectivity and various cellular processes such as 
 autophagy. 

 Geroprotective activities of chloroquine 

 Li  et  al.  reported  the  geroprotective  e�ects  of  low-dose  CQ  on  aged  rats  6  . 
 These  studies  were  inspired  by  a  perspective  article  published  at  the  height 
 of  the  COVID-19  pandemic  by  Sargiacomo  et  al.  in  2020  7  .  This  British 
 group  sought  to  explain  the  considerably  higher  mortality  rate  in 
 COVID-19  patients  with  advanced  chronological  age  prior  to  the 
 development  of  safe  vaccines.  They  pointed  out  that  the  proposed 
 SARS-Cov-2  viral  receptors,  CD26  and  ACE2,  were  associated  with 
 senescence  8,  9  .  Furthermore,  at  the  time,  azithromycin,  quercetin,  and  HCQ 
 were  proposed  as  "o�-the-shelf"  treatments  for  SARS-CoV2  infection  10  . 
 Quercetin  has  a  senolytic  activity  11  and  HCQ  is  known  to  inhibit 
 beta-galactosidase,  a  marker  of  senescence  12  .  Although  early  and 
 questionable  trials  demonstrated  some  bene�t  of  HCQ  13  for  SARS-CoV2, 
 subsequent  well-controlled  trials  demonstrated  limited,  if  any,  bene�t  14,  15  . 
 However,  it  is  important  to  note  that  investigation  of  the  role  of  the 
 autophagy pathway in viral pathogenesis continues  16  . 

 To  investigate  the  geroprotective  e�ects  of  HCQ,  Li  et  al.  treated 
 24-month-old  Sprague  Dawley  male  rats  (n  =  9)  with  CQ  (0.1  mg/kg,  in
 drinking  water)  twice  weekly  for  5  months  6  .  Compared  to  controls  (n  =
 13),  the  treated  animals  exhibited  a  6%  increase  in  medial  survival  and  13%
 increase in maximum lifespan (p = 0.02)  6  .

 Related  to  the  work  of  Li  et  al.,  Doeppner  et  al.  (2022)  also  reported  a 
 chloroquine-mediated  increase  in  the  lifespan  of  rodents,  in  this  case  mice  17  . 
 Work  by  Fifan  et  al.  18  and  others  19,  20  demonstrated  that  the  polyamine 
 spermidine  increased  the  maximum  life  span  of  C.  elegans  and  the  median 
 life  span  of  mice  (~10%).  Because  spermidine  increases  autophagy,  they 
 hypothesized  that  treatment  with  chloroquine,  an  inhibitor  of  autophagy, 
 would  shorten  the  lifespan  of  mice.  Remarkably,  addition  of  chloroquine 
 (50  mg/kg)  to  the  drinking  water  extended  overall  lifespan  of  middle-aged 

 Berkeley Pharma Tech Journal of Medicine |  3 



 male  NMRI  mice  (n  =  28;  treatment  initiated  at  age  500  days)  by  11.4% 
 (786  days)  compared  to  control  mice  (n  =  28;  689  days,  p  =  0.0002). 
 Median  life  span  of  the  middle-aged  mice  increased  by  11.4%.  Studies  of 
 chloroquine  by  these  two  groups  and  other  data  dating  back  a  couple 
 decades  suggest  the  e�ect  is  real,  although  the  precise  mechanism  is  not 
 clear.  Mechanistic  studies  carried  out  by  both  groups  suggest  a  variety  of 
 mechanisms, though this "ball of yarn" is far from being unraveled. 

 Mechanism studies 

 As  noted  above,  CQ  treatment  was  initiated  at  age  500  days  when  the  mice 
 weighed  on  average  ~35  gm.  Over  the  next  100  days,  the  control  animals 
 gained  weight,  reaching  a  maximum  of  45  gm.  In  contrast,  the  CQ-treated 
 animals  did  not  gain  signi�cant  weight  over  the  duration  of  the  experiment 
 (almost  800  days).  While  the  control  animals  consumed  more  liquid  (p  = 
 0.002),  the  food  consumed  by  both  groups  was  equal  (~4  gm/day)  ruling 
 out  the  idea  that  CQ  somehow  reduced  food  intake  through  an  arti�cial 
 "calorie restriction" e�ect. 

 Previously,  CQ  (at  60  mg/kg)  was  reported  to  impair 
 autophagosome-lysosome  fusion  rather  than  a�ecting  the  acidity  and/or 
 degradative  activities  of  lysosomes  21  .  In  addition,  HCQ  treatment  was 
 associated  with  "autophagy-independent"  disorganization  of  the  Golgi  and 
 endo-lysosomal  systems,  with  predominant  Golgi  disorganization  seen  in 
 kidney  and  intestinal  tissues.  The  microtubule-associated  protein  I  light 
 chain  (LC3)  family  of  proteins  (LC3A,  B,  C)  22  is  the  major  structural 
 protein  family  of  autophagosome  membranes.  LC3-II  is  generated  by  the 
 conjugation  of  cytosolic  LC3-I  to  phosphatidylethanolamine  on  the  surface 
 of  nascent  autophagosomes.  Doeppner  et  al.  showed  that  the  CQ-treated 
 mice  exhibited  a  dose-dependent  increase  in  LC3B-II  as  well  as  p62  in  the 
 liver  and  heart,  as  con�rmed  by  transmission  electron  microscopy  17  . 
 Curiously,  the  treated  animals  exhibited  increased  liver  glycogen  and 
 reduced  serum  insulin  growth  factor  binding  protein  3  (IGFBP3),  though 
 no  di�erence  in  IGF-1,  IRS,  or  growth  hormone  levels  23,  24  .  CQ  treatment 
 elicited a decrease in glycogenolysis in the liver. 

 Berkeley Pharma Tech Journal of Medicine |  4 



 IGFBP3  binds  IGF1  and  IGF2  to  modulate  their  binding  to  the  IGF-1 
 receptor.  While  IGFBP3  levels,  like  IGFs,  are  regulated  by  GH,  expression 
 in  the  liver  is  GH-independent  25  .  IGFB3  mediates  a  plethora  of  other 
 activities  via  its  binding  to  a  number  of  proteins  and  its  interaction  with 
 various  cell  surface  and  nuclear  signaling  pathways.  Several  labs  have 
 demonstrated a bene�cial role for reduced IGFB3 in senescence  26, 27, 28  . 

 Li  et  al.  found  that  low-dose  CQ  (0.1  mg/kg  given  twice  a  week)  extended 
 the  lifespan  of  aged  rats  when  given  in  late  middle  age  6  .  This  dose  is 
 ~100-fold  lower  than  doses  typically  given  as  a  putative  autophagy  inhibitor 
 in  cancer  29  .  Qian  et  al.  attributed  the  geroprotective  e�ect  of  CQ  to  ATM 
 activation  leading  to  enhanced  DNA  damage  repair  within  their  C.  elegans 
 and  progeria  mouse  strain  models  30  .  Others  have  shown  that  activation  of 
 ATM  by  CQ  can  slow  atherosclerosis,  improve  insulin  sensitivity,  and 
 rescue glucose intolerance in type 2 diabetes (T2D)  31,  32, 33  . 

 Li  et  al.  studied  the  transcriptomes  from  CQ-treated  and  control  old  rats  to 
 de�ne  CQ-induced,  di�erentially  expressed  genes  so-called  “CQ  DEGs” 
 across  multiple  tissues.  For  example,  40%  of  kidney-speci�c  aged  genes,  30% 
 of  small  intestine-speci�c  aged  genes,  and  20%  of  liver-speci�c  aged  genes 
 were  "rescued"  by  CQ  treatment.  These  changes  were  consistent  with  the 
 reduced  �brosis  and  improved  histology  of  the  kidneys  compared  to  other 
 tissues.  Contrary  to  expectation,  CQ  treatment  augmented  a  number  of 
 genes  associated  with  various  cardiac  diseases  (e.g.  heart  failure,  cardiac 
 arrhythmias,  ischemic  cardiomyopathy  (Caps2),  hypertrophic 
 cardiomyopathy,  and  cardiac  arrhythmias  (Myh7).  Thus,  CQ  treatment 
 may actually mediate pro-aging activity in certain tissues  6  . 

 Summary 

 A  number  of  labs  have  studied  several  animal  species  to  generate  data 
 suggesting  that  CQ  can  mediate  a  pro-longevity  e�ect.  Mechanistic  studies 
 indicate  that  multiple  mechanisms  are  at  play,  each  addressing  a  hallmark  of 
 aging  34  .  While  CQ  and  HCQ  are  familiar  to  cell  biologists  as  prototypic 

 Berkeley Pharma Tech Journal of Medicine |  5 



 lysosomotropic  e�ect  tool  compounds,  numerous  diverse  studies  highlight 
 the  plethora  of  other  activities  mediated  by  CQ.  Isolated  papers  over  the 
 past  20  years  have  identi�ed  non-autophagy-mediated  e�ects  of  CQ.  For 
 example,  CQ  improves  vasculogenesis  35  ,  insulin  metabolism  31  ,  �brosis  36  , 
 reduces  oxidative  stress  37  ,  modulates  autophagic  �ux  21  ,  boosts  DNA  repair 
 via  STM  30  ,  and  attenuates  atherogenesis  33  to  name  a  few.  When  we  began 
 looking  into  this  story,  we  sought  a  unifying  mechanism,  pathway,  target, 
 etc.  to  explain  the  increased  lifespans.  Unfortunately,  at  the  present  time, 
 descriptive  studies  nominate  many  parallel  mechanisms.  The  detailed 
 transcriptome  studies  of  Li  et  al.  show  quite  variable  tissue  speci�c  patterns, 
 with  some  that  are  bene�cial  for  health  span  and  others  that  are  consistent 
 with  cardiac  diseases  6  .  Of  course,  investigating  the  geroprotective  e�ects  of 
 CQ  using  Horvath  or  other  methylation  clocks  might  lead  to  interesting 
 �ndings. 

 Medical Implications 

 As  noted  above,  CQ  and  HCQ  are  widely  used  drugs  38  .  The  studies  of  Li  et 
 al.  and  Doeppner  et  al.  support  further,  possibly  human  studies  of  these 
 drugs.  On  October  8–13,  2013,  a  workshop  entitled  ‘Interventions  to  Slow 
 Aging  in  Humans:  Are  We  Ready?’  was  held  in  Erice,  Italy  39  .  At  the  time,  a 
 number  of  interventions  were  deemed  worthy  of  human  clinical  trials. 
 Since  then,  some  of  these  ideas  have  been  put  to  the  test  or  are  being  tested  . 
 With  regard  to  development  of  CQ/HCQ,  suitable  biomarkers  will  need  to 
 be  validated.  At  low  doses,  CQ  or  HCQ  seem  to  qualify  for  evaluation  in 
 humans.  However,  the  safety  pro�le  of  this  class  of  drugs  will  need  to  be 
 considered.  For  instance,  periodic  eye  exams  and  cardiac  monitoring  are 
 routine  40  at  doses  commonly  used  in  rheumatology  38  .  Clearly  these 
 anti-malarials have come a long way from the rainforests of South America! 

 Berkeley Pharma Tech Journal of Medicine |  6 



 References 

 1. Plantone D, Koudriavtseva T. Current and future use
 of chloroquine and hydroxychloroquine in infectious,
 immune, neoplastic, and neurological diseases: A 
 mini-review.  Clinical Drug Investigation  .
 2018;38(8):653-671. doi:10.1007/s40261-018-0656-y

 2. Rasmussen C, Alonso P, Ringwald P. Current and
 emerging strategies to combat antimalarial resistance.
 Expert Review of Anti-infective Therapy  . 
 2021;20(3):353-372.
 doi:10.1080/14787210.2021.1962291

 3. Chou AC, Fitch CD. Heme polymerase: Modulation
 by chloroquine treatment of a rodent malaria.  Life 
 Sciences  . 1992;51(26):2073-2078.
 doi:10.1016/0024-3205(92)90158-l

 4. Slater AF, Cerami A. Inhibition by chloroquine of a
 novel haem polymerase enzyme activity in malaria 
 trophozoites.  Nature  . 1992;355(6356):167-169.
 doi:10.1038/355167a0

 5. Coronado LM, Nadovich CT, Spadafora C. Malarial 
 hemozoin: From target to tool.  Biochimica et Biophysica 
 Acta (BBA) - General Subjects  . 2014;1840(6):2032-2041.
 doi:10.1016/j.bbagen.2014.02.009

 6. Li W, Zou Z, Cai Y, et al. Low-dose chloroquine
 treatment extends the lifespan of aged rats.  Protein  &
 Cell  . 2022;13(6):454-461.
 doi:10.1007/s13238-021-00903-1

 7. Sargiacomo C, Sotgia F, Lisanti MP. Covid-19 and
 Chronological Aging: Senolytics and other anti-aging
 drugs for the treatment or prevention of Corona virus
 infection?  Aging  . 2020;12(8):6511-6517.
 doi:10.18632/aging.103001

 8. Kim KM, Noh JH, Bodogai M, et al. Identi�cation of
 senescent cell surface targetable protein DPP4.  Genes  &
 Development  . 2017;31(15):1529-1534.
 doi:10.1101/gad.302570.117

 9. Guy JL, Lambert DW, Turner AJ, Porter KE.
 Functional angiotensin-converting enzyme 2 is expressed
 in human cardiac myo�broblasts.  Experimental 
 Physiology  . 2008;93(5):579-588.
 doi:10.1113/expphysiol.2007.040139

 10. Cavalcante MB, Saccon TD, Nunes ADC, et al. 
 Dasatinib plus quercetin prevents uterine age-related
 dysfunction and �brosis in mice.  Aging  . 
 2020;12(3):2711-2722. doi:10.18632/aging.102772

 11. Zoico E, Nori N, Darra E, et al. Senolytic e�ects of
 quercetin in an in vitro model of pre-adipocytes and
 adipocytes induced senescence.  Scientific Reports  .
 2021;11(1). doi:10.1038/s41598-021-02544-0

 12. Kurz DJ, Decary S, Hong Y, Erusalimsky JD.
 Senescence-associated (beta)-galactosidase re�ects an 
 increase in lysosomal mass during replicative ageing of
 human endothelial cells.  Journal of Cell Science  . 
 2000;113(20):3613-3622. doi:10.1242/jcs.113.20.3613

 13. Gautret P, Lagier J-C, Parola P, et al. 
 Hydroxychloroquine and azithromycin as a treatment of
 COVID-19: Results of an open-label non-randomized 
 clinical trial.  International Journal of Antimicrobial 
 Agents  . 2020. doi:10.1101/2020.03.16.20037135

 14. Boulware DR, Pullen MF, Bangdiwala AS, et al. A 
 randomized trial of hydroxychloroquine as postexposure
 prophylaxis for covid-19.  New England Journal of
 Medicine  . 2020;383(6):517-525.
 doi:10.1056/nejmoa2016638

 15. Tang W, Cao Z, Han M, et al. Hydroxychloroquine
 in patients with mainly mild to moderate coronavirus
 disease 2019: Open label, Randomised Controlled Trial.
 BMJ  . 2020:m1849. doi:10.1136/bmj.m1849

 16.He W, Gao Y, Zhou J, Shi Y, Xia D, Shen H-M.
 Friend or foe? implication of the autophagy-lysosome
 pathway in SARS-COV-2 infection and COVID-19.
 International Journal of Biological Sciences  .
 2022;18(12):4690-4703. doi:10.7150/ijbs.72544

 Berkeley Pharma Tech Journal of Medicine |  7 



 17. Doeppner TR, Coman C, Burdusel D, et al. 
 Long-term treatment with chloroquine increases lifespan
 in middle-aged male mice possibly via autophagy 
 modulation, proteasome inhibition and glycogen
 metabolism.  Aging  . 2022;14(10):4195-4210.
 doi:10.18632/aging.204069

 18. Filfan M, Olaru A, Udristoiu I, et al. Long-term
 treatment with spermidine increases health span of
 middle-aged Sprague-Dawley male rats.  GeroScience. 
 2020;42(3):937-949. doi:10.1007/s11357-020-00173-5

 19. Eisenberg T, Knauer H, Schauer A, et al. Induction
 of autophagy by spermidine promotes longevity.  Nature
 Cell Biology  . 2009;11(11):1305-1314.
 doi:10.1038/ncb1975

 20. Eisenberg T, Abdellatif M, Schroeder S, et al.
 Cardioprotection and lifespan extension by the natural
 polyamine spermidine.  Nature Medicine  . 
 2016;22(12):1428-1438. doi:10.1038/nm.4222

 21. Mauthe M, Orhon I, Rocchi C, et al. Chloroquine
 inhibits autophagic �ux by decreasing
 autophagosome-lysosome fusion.  Autophagy  . 
 2018;14(8):1435-1455.
 doi:10.1080/15548627.2018.1474314

 22. Yoshii SR, Mizushima N. Monitoring and measuring
 autophagy.  International Journal of Molecular Sciences  .
 2017;18(9):1865. doi:10.3390/ijms18091865

 23. Brown-Borg HM, Bartke A. GH and igf1: Roles in 
 energy metabolism of long-living GH mutant mice.  The
 Journals of Gerontology Series A: Biological Sciences and 
 Medical Sciences  . 2012;67A(6):652-660.
 doi:10.1093/gerona/gls086 

 24. Junnila RK, List EO, Berryman DE, Murrey JW,
 Kopchick JJ. The GH/IGF-1 axis in ageing and
 longevity.  Nature Reviews Endocrinology  . 
 2013;9(6):366-376. doi:10.1038/nrendo.2013.67

 25. Olivecrona H, Hilding A, Ekström Christina, et al.
 Acute and short-term e�ects of growth hormone on
 insulin-like growth factors and their binding proteins:
 Serum levels and hepatic messenger ribonucleic acid 
 responses in humans1.  The Journal of Clinical 
 Endocrinology &amp; Metabolism  . 1999;84(2):553-560.
 doi:10.1210/jcem.84.2.5466

 26. Hong S, Kim M-M. IGFBP-3 plays an important 
 role in senescence as an aging marker.  Environmental
 Toxicology and Pharmacology  . 2018;59:138-145.
 doi:10.1016/j.etap.2018.03.014

 27. Hong S, Kim M-M. IGFBP-3 plays an important 
 role in senescence as an aging marker.  Environmental
 Toxicology and Pharmacology  . 2018;59:138-145.
 doi:10.1016/j.etap.2018.03.014

 28. Yamada PM, Mehta HH, Hwang D, Roos KP,
 Hevener AL, Lee KW. Evidence of a role for insulin-like
 growth factor binding protein (IGFBP)-3 in metabolic
 regulation.  Endocrinology  . 2010;151(12):5741-5750.
 doi:10.1210/en.2010-0672

 29. Solomon VR, Lee H. Chloroquine and its analogs: A
 new promise of an old drug for e�ective and safe cancer
 therapies.  European Journal of Pharmacology  . 
 2009;625(1-3):220-233.
 doi:10.1016/j.ejphar.2009.06.063

 30. Qian M, Liu Z, Peng L, et al. Boosting ATM activity
 alleviates aging and extends lifespan in a mouse model of
 progeria.  eLife  . 2018;7. doi:10.7554/elife.34836

 31. Emami J, Gerstein HC, Pasutto FM, Jamali F.
 Insulin-sparing e�ect of hydroxychloroquine in diabetic
 rats is concentration dependent  . Canadian Journal of 
 Physiology and Pharmacology  . 1999;77(2):118-123.
 doi:10.1139/y98-146

 32. Schneider JG, Finck BN, Ren J, et al.
 ATM-dependent suppression of stress signaling reduces
 vascular disease in metabolic syndrome.  Cell

 Berkeley Pharma Tech Journal of Medicine |  8 



 Metabolism  . 2006;4(5):377-389. 
 doi:10.1016/j.cmet.2006.10.002 

 33. Razani B, Feng C, Semenkovich CF. P53 is required
 for chloroquine-induced atheroprotection but not
 insulin sensitization.  Journal of Lipid Research  .
 2010;51(7):1738-1746. doi:10.1194/jlr.m003681

 34. López-Otín C, Blasco MA, Partridge L, Serrano M, 
 Kroemer G. The hallmarks of aging.  Cell. 
 2013;153(6):1194-1217. doi:10.1016/j.cell.2013.05.039

 35. Maes H, Kuchnio A, Peric A, et al. Tumor vessel
 normalization by chloroquine independent of
 autophagy.  Cancer Cell  . 2014;26(2):190-206.
 doi:10.1016/j.ccr.2014.06.025

 36. He W, Wang B, Yang J, et al. Chloroquine improved 
 carbon tetrachloride-induced liver �brosis through its
 inhibition of the activation of hepatic stellate cells: Role
 of autophagy.  Biological and Pharmaceutical Bulletin  . 
 2014;37(9):1505-1509. doi:10.1248/bpb.b14-00297

 37. Shen H, Wu N, Wang Y, et al. Chloroquine 
 attenuates paraquat-induced lung injury in mice by
 altering in�ammation, oxidative stress and �brosis.
 International Immunopharmacology  . 2017;46:16-22.
 doi:10.1016/j.intimp.2017.02.020

 38. Schrezenmeier E, Dörner T. Mechanisms of action of
 hydroxychloroquine and chloroquine: Implications for
 rheumatology. Nature Reviews Rheumatology. 
 2020;16(3):155-166. doi:10.1038/s41584-020-0372-x

 39. Longo VD, Antebi A, Bartke A, et al. Interventions
 to Slow Aging in Humans: Are We Ready?.  Aging Cell  .
 2015;14(4):497-510. doi:10.1111/acel.12338

 40. Wozniacka A, Cygankiewicz I, Chudzik M,
 Sysa-Jędrzejowska A, Wranicz JK. The cardiac safety of
 chloroquine phosphate treatment in patients with
 systemic lupus erythematosus: The in�uence on
 arrhythmia, heart rate variability                 and 

 repolarization parameters.  Lupus  . 2006;15(8):521-525. 
 doi:10.1191/0961203306lu2345oa 

 Berkeley Pharma Tech Journal of Medicine |  9 




