Singh Et Al 2023 - Science - Taurine Deficiency As A Driver of Aging

RES EARCH
◥ which taurine supplementation improved

RESEARCH ARTICLE SUMMARY the health span and life span revealed that
taurine positively affected several hallmarks of
AGING aging. Taurine reduced cellular senescence,
protected against telomerase deficiency, sup-
Taurine deficiency as a driver of aging pressed mitochondrial dysfunction, decreased
DNA damage, and attenuated inflammation.
Parminder Singh†*, Kishore Gollapalli†, Stefano Mangiola‡, Daniela Schranner‡, An association analysis of metabolite clinical
Mohd Aslam Yusuf‡, Manish Chamoli‡ et al. risk factors in humans showed that lower
taurine, hypotaurine, and N-acetyltaurine con-
centrations were associated with adverse health,
INTRODUCTION: Aging is an inevitable multi- RESULTS: Blood concentration of taurine de- such as increased abdominal obesity, hyper-
factorial process. Aging-related changes man- clines with age in mice, monkeys, and hu- tension, inflammation, and prevalence of type
ifest as the “hallmarks of aging,” cause organ mans. To investigate whether this decline 2 diabetes. Moreover, we found that a bout of
functions to decline, and increase the risk of contributes to aging, we orally fed taurine or exercise increased the concentrations of taur-
disease and death. Aging is associated with a control solution once daily to middle-aged ine metabolites in blood, which might partially
Downloaded from https://www.science.org at Liverpool John Moores University on September 25, 2023
systemic changes in the concentrations of wild-type female and male C57Bl/6J mice until underlie the antiaging effects of exercise.
molecules such as metabolites. However, the end of life. Taurine-fed mice of both sexes
whether such changes are merely the con- survived longer than the control mice. The CONCLUSION: Taurine abundance decreases
sequence of aging or whether these molecules median life span of taurine-treated mice in- during aging. A reversal of this decline through
are drivers of aging remains largely unex- creased by 10 to 12%, and life expectancy at taurine supplementation increases health span
plored. If these were blood-based drivers of 28 months increased by about 18 to 25%. A and life span in mice and worms and health
aging, then restoring their concentration or meaningful antiaging therapy should not only span in monkeys. This identifies taurine de-
functions to “youthful” levels could serve as improve life span but also health span, the ficiency as a driver of aging in these species.
an antiaging intervention. period of healthy living. We, therefore, inves- To test whether taurine deficiency is a driver
tigated the health of taurine-fed middle-aged of aging in humans as well, long-term, well-
RATIONALE: Taurine, a semiessential micro- mice and found an improved functioning of controlled taurine supplementation trials that
nutrient, is one of the most abundant amino bone, muscle, pancreas, brain, fat, gut, and measure health span and life span as outcomes
acids in humans and other eukaryotes. Ear-
lier studies have shown that the concen-
immune system, indicating an overall increase
in health span. We observed similar effects in
are required.
▪
tration of taurine in blood correlates with monkeys. To check whether the observed effects The list of author affiliations is available in the full article online.
health, but it is unknown whether blood tau- of taurine transcended the species boundary, *Corresponding author. Email: vky2101@cumc.columbia.edu
rine concentrations affect aging. To address we investigated whether taurine supplementa- †These authors contributed equally to this work.
‡These authors contributed equally to this work.
this gap in knowledge, we measured the tion increased life span in worms and yeast.
Cite this article as P. Singh et al., Science 380, eabn9257
blood concentration of taurine during aging Although taurine did not affect the replicative (2023). DOI: 10.1126/science.abn9257
and investigated the effect of taurine supple- life span of unicellular yeast, it increased life
mentation on health span and life span in span in multicellular worms. Investigations READ THE FULL ARTICLE AT
several species. into the mechanism or mechanisms through https://doi.org/10.1126/science.abn9257
Taurine supplementation makes animals healthier and live longer Pancr Taurine deficiency associates with poor health
e
Bon eas
Taurine abundance
Diabetes
e
Gu
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Mu
BMI Obesity
Health span
Age
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High glucose Liver disease

Brai
En
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Taurine
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supplementation
une Hypertension
Abdominal
Fat Imm obesity
Taurine Effects on aging hallmarks

Control solution Analysis of life span Senescence Inflammation
Intercellular communication
Telomere shortening Missing piece: Randomized clinical trial
Nutrient sensing
Yeast Worm Mouse Taurine Epigenetic changes Taurine
Genomic instability
Survival
Loss of proteostasis
Mitochondrial dysfunction
Age Stem cell exhaustion
Taurine deficiency as a driver of aging. Taurine concentration in blood declines with aging (top left). A reversal of this drop through taurine supplementation
increased healthy life span in mice and worms but not in yeast (bottom left and top middle). Taurine supplementation affected several hallmarks of aging (middle).
In humans, lower taurine concentrations were associated with multiple diseases (top right). A randomized controlled clinical trial in humans is warranted to assess
the antiaging effects of taurine (bottom right). BMI, body mass index.
Singh et al., Science 380, 1028 (2023) 9 June 2023 1 of 1

RES EARCH
◥ a correction to its youthful levels would de-

RESEARCH ARTICLE lay aging and increase healthy life span.
Taurine (2–aminoethanesulfonic acid), a
AGING semiessential micronutrient, is one of the most
abundant amino acids found in organisms
Taurine deficiency as a driver of aging across eukaryotic phyla (18–22). In mamma-
lian cells, taurine is produced from cysteine
Parminder Singh1†‡, Kishore Gollapalli2†§, Stefano Mangiola3,4,5,6¶, Daniela Schranner7,8¶, through the action of cysteine sulfinic acid
Mohd Aslam Yusuf9¶, Manish Chamoli10¶, Sting L. Shi2#, Bruno Lopes Bastos11, Tripti Nair12, decarboxylase (CSAD) (20). Taurine can also
Annett Riermeier7, Elena M. Vayndorf13, Judy Z. Wu13, Aishwarya Nilakhe1, Christina Q. Nguyen13, be obtained from the diet and is taken up by
Michael Muir13, Michael G. Kiflezghi13, Anna Foulger10, Alex Junker14, Jack Devine14, Kunal Sharan15, cells through taurine transporters (20). Taur-
Shankar J. Chinta10, Swati Rajput16, Anand Rane10, Philipp Baumert7, Martin Schönfelder7, ine deficiency during early life causes func-
Francescopaolo Iavarone17, Giorgia di Lorenzo17, Swati Kumari1, Alka Gupta1, Rajesh Sarkar1, tional impairments in skeletal muscle, eye,
Costerwell Khyriem18,19, Amanpreet S. Chawla20,21, Ankur Sharma18,19, Nazan Sarper22, and the central nervous system (23–26) that
Naibedya Chattopadhyay16, Bichitra K. Biswal1, Carmine Settembre17,23, Perumal Nagarajan24,25, are related to aging-associated disorders. More-
Kimara L. Targoff26, Martin Picard14, Sarika Gupta1, Vidya Velagapudi27, Anthony T. Papenfuss3,4, over, concentrations of taurine and its metab-
Alaattin Kaya28, Miguel Godinho Ferreira11, Brian K. Kennedy29,30,31, Julie K. Andersen10, olites decline in some tissues with age, and
Gordon J. Lithgow10, Abdullah Mahmood Ali32, Arnab Mukhopadhyay12, Aarno Palotie27,33,34, acute taurine supplementation in young ani-
Gabi Kastenmüller8, Matt Kaeberlein13, Henning Wackerhage7, Bhupinder Pal3,4,5,6, Vijay K. Yadav1,2,15,35* mals enhances the functions of several organs
(27–35). Given the decline in taurine abun-
Aging is associated with changes in circulating levels of various molecules, some of which remain dance during aging and its known health ef-
undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and fects, we aimed to find out whether taurine
humans. A reversal of this decline through taurine supplementation increased the health span (the period deficiency is a driver of aging and affects healthy
of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced life span.
cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction,
decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations Results
correlated with several age-related diseases and taurine concentrations increased after acute endurance Decline of serum concentrations of taurine with
exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in age in mice, monkeys, and humans
worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted To comprehensively study whether taurine
to test whether taurine deficiency might drive aging in humans. abundance influences healthy life span, we
measured blood taurine concentrations at dif-
A
ferent ages in mice, monkeys, and humans. In
ccording to the World Population Pros- adenine dinucleotide (NAD) precursors, and C57Bl/6J wild-type (WT) mice, serum taurine
pects of the United Nations, the number senolytics (2–6, 12). concentrations declined from 132.3 ± 14.2 ng/
of people aged 65 and older will increase Aging is a complex process that affects all ml at 4 weeks to 40.2 ± 7.1 ng/ml at 56 weeks,
from 1 in 11 in 2019 to 1 in 6 in 2050 (1). organs (13, 14). The age-induced decline in which correlates negatively with age (slope =
Although this is a success of modern organ functions involves several cell-autonomous −25.7; p < 2 × 10−16) (Fig. 1A). In 15-year-old
medicine and of government policies, it is vital events termed “hallmarks of aging.” The cen- monkeys, serum taurine concentrations were
to ensure that the elderly also remain healthy, tral hallmarks include genomic instability, 85% lower than in 5-year-old monkeys (Fig. 1B).
because this will increase the quality of life deregulated nutrient sensing, mitochondrial Likewise, taurine concentrations in elderly
and reduce the costs associated with societal dysfunction, stem cell exhaustion, and accumu- humans were decreased by more than 80%
aging (2–5). Over the past two decades, efforts lation of senescent cells (13). Aging-associated compared with the concentration in serum
to identify antiaging interventions that reduce decline in organ functions also results from of younger individuals (Fig. 1C).
morbidity and increase life span have intensi- changes in the concentrations of endogenous
fied (2–11). This has led to the identification of metabolites, hormones, and micronutrients in Taurine supplementation increases the life span
compounds that may increase healthy life span blood (15–17). However, it is unclear whether of mice
(the period of life span spent in good health) these changes are passengers or drivers of aging. To determine whether the observed drop in
such as rapamycin, metformin, nicotinamide If a molecule in blood is a driver of aging, then taurine concentration contributes to aging, we
1
Metabolic Research Laboratories, National Institute of Immunology, New Delhi, India. 2Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. 3The Walter and Eliza Hall
Institute of Medical Research, Parkville, VIC, Australia. 4Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. 5School of Cancer Medicine, La Trobe University, Bundoora, VIC,
Australia. 6Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia. 7Exercise Biology Group, Technical University of Munich, Munich, Germany. 8Institute of Computational Biology,
Helmholtz Zentrum München, Neuherberg, Germany. 9Department of Bioengineering, Integral University, Lucknow, India. 10Buck Institute for Research on Aging, Novato, CA, USA. 11Institute for Research on
Cancer and Aging of Nice (IRCAN), Nice, France. 12Molecular Aging Laboratory, National Institute of Immunology, New Delhi, India. 13Department of Laboratory Medicine and Pathology, University of
Washington, Seattle, WA, USA. 14Department of Neurology, Columbia University, New York, NY, USA. 15Mouse Genetics Project, Wellcome Sanger Institute, Cambridge, UK. 16Division of Endocrinology,
CSIR-Central Drug Research Institute, Lucknow, India. 17Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy. 18Harry Perkins Institute of Medical Research, Perth, WA, Australia. 19Curtin
Medical School, Curtin University, Perth, WA, Australia. 20Immunobiology Laboratory, National Institute of Immunology, New Delhi, India. 21MRC-Protein Phosphorylation and Ubiquitination Unit, University of
Dundee, Dundee, UK. 22Pediatrics and Pediatric Hematology, Kocaeli University Hospital, Kocaeli, Turkey. 23Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. 24Primate
Research Facility, National Institute of Immunology, New Delhi, India. 25Small Animal Research Facility, National Institute of Immunology, New Delhi, India. 26Division of Cardiology, Department of Pediatrics,
Columbia University, New York, NY, USA. 27Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. 28Department of Biology, Virginia Commonwealth University, Richmond,
VA, USA. 29Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 30Centre for Healthy Longevity, National University
Health System, Singapore, Singapore. 31Departments of Biochemistry and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 32Department of Medicine,
Columbia University Irving Medical Center, New York, NY, USA. 33Broad Institute of Harvard and MIT, Cambridge, MA, USA. 34Analytic and Translational Genetics Unit, Massachusetts General Hospital,
Boston, MA, USA. 35Department of Genetics and Development, Columbia University, New York, NY, USA.
*Corresponding author. Email: vky2101@cumc.columbia.edu
†These authors contributed equally to this work. ‡Present address: Buck Institute for Research on Aging, Novato, CA, USA. §Present address: Department of Microbiology and Immunology, Columbia University, New York,
NY, USA. ¶These authors contributed equally to this work. #Present address: Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA.
Singh et al., Science 380, eabn9257 (2023) 9 June 2023 1 of 11

RES EARCH | R E S E A R C H A R T I C L E
A B C
300 p < 2.2e-16
Mus musculus 150
p < 2e-16
Macaca mulatta 100 Young (5.0±1.8 yrs)
Serum taurine ( mol/L)

Serum taurine (ng/ml)
Old (15.0±1.5 yrs)
Serum taurine (ng/ml)
n=7
200
100
50 Homo sapiens
50 100
**
n=6
0 0
Age (Weeks) 0 20 40 60 Age (Years) 0 20 40 60
D E
+
Mus musculus WT + Vehicle (n=62) WT + Vehicle (n=64)
100
100 p < 0.00001 WT + Taurine (n=60) p < 0.0001 WT + Taurine (n=60)
Vehicle/Taurine Vehicle/Taurine
Survival (%)
75
Survival (%)
75
50
50
25
25
0 0
Age (Months) 12 16 20 24 28 32 36 40 Age (Months) 12 16 20 24 28 32 36 40
Q80WP8
F G H
Q6ZQY3 H. sapiens GADL1
DL1
T=Taurine T=Taurine
M.
ta GA
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muscu
T 0 M (n=203) T 0 M (n=40)
1L4
GA
mulat
sad
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C. elegans S. cerevisiae
+
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T 10 M (n=166) T 300 M (n=40)
CS
ga
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s
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185
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op
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100 scu
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3
mu
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M.
Survival probability (RLS)
T 150 M (n=205) GA
D F6
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0
1 D BE
Q9 icus Cs
ad
80 T 300 M (n=267) P18088 R. 11 R.
norveg
norvegicus Q646
0.75 Gad1
Survival (%)
P20228 D. melanogaster Gad1

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60 P48318 M. mus G5ED
Median lifespan Mean RLS AD1
B7 C . eleg
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19.52±0.40 0.50 4 M. m 1
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ga
23.19±039***
Q7
.m
0.00
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0
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GA
Generation
Q05683
Age (days) 0 10 20 30 40 50
320
0 5 10 15 20 25 30 35
D2
D2
P48
9532
Fig. 1. Taurine deficiency is a driver of aging in evolutionarily divergent spe- yeast cultured on YPD plates with different concentrations of taurine (0, 300, 1000,
cies. (A to C) Serum taurine levels in female mice at different ages (A), in young and 100,000 mM). (H) Phylogenetic analysis of taurine biosynthesis enzymes in
(5-year-old) and old (15-year-old) female monkeys (B), and in humans at different eukaryotes. Statistical analysis details are as follows: The OASIS software (https://sbi.
ages (C). In (A) and (C), shaded regions indicate standard error. (D and E) Life-span postech.ac.kr/oasis) was used to calculate p values using a log rank test (the Mantel-
assay of middle-aged (14-month-old) WT female (D) and male (E) C57Bl/6J mice Cox method) in mice and worm experiments, and a Wilcoxon rank-sum test was
orally fed taurine (1000 mg per kg body weight per day) at 10:00 am until the end of used to calculate p values in yeast RLS assays. N values are shown within the panels.
life. (F) Life-span assay of WT nematodes that were fed diet supplemented with All values are means ± SEM. ns indicates not significant. ***p ≤ 0.001, **p ≤ 0.01,
different concentrations of taurine (0, 10, 50, 100, 150, and 300 mM). (G) RLS assay in and *p ≤ 0.05* are versus WT or control.
orally administered control solution or taurine 10 to 12%, and life expectancy at 28 months Taurine supplementation increases the life span
at 1000 mg per kg body weight (T1000), once increased by 18 to 25% (Fig. 1, D and E). Me- of worms but not yeast
daily at 10:00 am, to 14-month-old (middle- dian life-span estimates for control female and The taurine biosynthetic pathway is evolution-
aged) C57Bl/6J WT female and male mice until male mice were consistent in two independent arily conserved among multicellular eukaryotes
the end of life. The dose and frequency of tau- cohorts (females: 871 to 885 days; males: 785 (21, 36). To find out whether taurine also af-
rine administration was selected based on a to 815 days). In these experiments, both con- fects aging in species other than mice, we con-
pilot study, which showed that when given trol and taurine-fed mice had ad libitum ac- ducted taurine supplementation experiments
once daily to middle-aged WT mice, this reg- cess to the same chow (Teklad Irradiated in lower species. First, we tested the effect of
imen increased the peak blood taurine con- 18% protein and 6% fat diet-2918). Thus, the taurine in worms, which also exhibit an age-
centrations to baseline concentrations in young improved survival of taurine-fed mice was associated decline in taurine (37). Taurine sup-
(4-week-old) mice (see materials and methods not a consequence of low survival of control plementation significantly extended both the
and fig. S1, A to D, for a description of these animals or differences in diet. Collectively, median and maximum life spans of Caenorhabditis
studies). Regardless of their sex, taurine-fed these results indicate that taurine deficiency elegans in a dose-dependent manner (Fig. 1F).
mice survived longer than control mice (Fig. 1, is a driver of aging in mice because its re- Longevity, calculated using the median life
D and E). The median life-span increase was versal increases life span. span of untreated and taurine-treated worms,

was extended by 10 to 23% in worms treated Taurine supplementation increases health span mice did not differ in body length and food
with higher taurine concentrations in four in- in aged WT female mice consumption (in weight-stable mice) or suffer
dependent worm cohorts and in two inde- A meaningful antiaging therapy should im- obvious toxic effects (as evidenced by a blinded
pendent laboratories (University of Washington, prove health span, or the period of healthy living histopathological scoring of tissue sections by
Seattle, WA, USA, and the National Institute of (2–5, 40). To assess the effects of taurine sup- a trained histopathologist) in multiple tissues
Immunology, New Delhi, India) (Fig. 1F and plementation on health span, we orally ad- compared with controls (fig. S2, B to D). Bone
fig. S1, E to G). We also investigated the effect ministered taurine at 500 (T500) and 1000 structure analysis through histology and mi-
of taurine on replicative life span (RLS) in bud- (T1000) mg per kg body weight per day to fe- crocomputed tomography (mCT) showed that
ding yeast, Saccharomyces cerevisiae, which is male mice once daily for 10 to 12 months, start- taurine treatment increased bone mass (bone
a unicellular eukaryote. In contrast to mice ing at the age of 14 months, and analyzed the volume divided by total volume percentage)
and worms, taurine supplementation did not health of bone, muscle, brain, pancreas, fat, gut, in both the spine and femur compared with
affect the RLS (38) of yeast cultured on nutrient- and the immune system through functional assays that in controls (Fig. 2C). A three-point bend-
rich yeast extract–peptone–dextrose (YPD) or tissue analysis of deceased animals (fig. S2A). ing test showed that femur maximal load and
plates or on a synthetic medium (Fig. 1G and stiffness—two surrogates of bone quality—
fig. S1, H to J). These results may be explained Reduced age-associated body-weight gain improved in taurine-treated mice compared
by organismal differences in taurine metabo- and improved bone mass in female mice with controls (Fig. 2D). Taurine also cured
lism. For example, the taurine metabolism treated with taurine osteoporosis and suppressed ovariectomy-
enzymes yeast glutamate decarboxylase (GAD) Taurine treatment suppressed age-associated induced body-weight gain in a rodent model
and mammalian CSAD diverged early during body-weight gain by ~10% in the T1000 group of menopause (fig. S2, E to G). This latter evi-
evolution (Fig. 1H) (39). Thus, although tau- compared with controls (Fig. 2A). Fat-pad dence indicates that the effect of taurine on
rine may not affect the RLS in unicellular eu- weight divided by body weight percentage health parameters in females might be linked
karyotes, its effect on life span is conserved was dose-dependently reduced in taurine- to its effect on body weight in other conditions
in invertebrates and mammals. treated mice (Fig. 2B). Taurine-administered of aging, such as menopause.
A 24 month-old B C
Gonadal fat Skeleton
In-life/
Once daily oral gavage 4
Terminal
Gonadal fat pad/BW (%)
14 month-old mice T0 (n=9) T500 (n=10) T1000 (n=8) T0 (n=4) T500 (n=5) T1000 (n=4)
T0 T500 T1000
analysis **
*
40
n=10
Body weight (g)
*
ns
30 2
n=10
n=10
20 1mm
10 3.26 ± 0.34 5.17 ± 0.50* 5.49 ± 0.37* 4.90 ± 0.43 7.21 ± 0.40* 7.84 ± 0.58*
0 0 Vertebra (BV/TV%) Femur (BV/TV%)

13 16 19 22 25
Age (months)
D Skeleton strength E Neuromuscular coordination F Grip strength G Anxiety H Memory

60 300 3 ** T0
** ** * * * * ** *
Femur maximum load (N)
15 ns
*
* * T500
Total hanging time (sec)
180
Complete fracture load (N)
15 *
Time spent in dark (sec)
Latency to fall (sec)
* * * 80 T1000
Grip Strength (g/g)
n=10
Immobility (sec)
Distance (meter)
n=10
n=5
n=5
n=10
n=5
n=9
n=10
5.0
n=10
Alterations (%)
40 ns
n=10
n=10
200
n=10
n=10
2 200
n=10
n=5
10
n=10
10 120
n=10
n=5
n=10
n=9
n=10
n=10
n=5
n=9
40
n=10
n=10
20 2.5 100
5 1 100
n=10
5 60
0 0 0 0 0 0 0 0 0
I Glucose homeostasis J GI Transit K Immunophenotype

T0 (n=10)
* * T0 (n=15) 100 * * 15 ** ** **
T500 (n=10) 150 * T500 (n=14) *
4 ns ns
*
Monocytes (X106/mm3)
Blood glucose (mg/dl)
1.5
Blood glucose (% of initial)
*
n=10
*
Granulocytes (X106/mm3)
T1000 (n=10) 120 T1000 (n=15)

WBC (X106/mm3)
300
n=15
n=10
n=10
Glucose (mg/dl)
n=10
GTT (AUCX100)
*
n=8
n=10
0.6
n=10
n=8
n=10
Time (hrs)
n=8
200 10
n=15
ITT (AUC)
n=14
100
1.0
n=10
*
n=10
200 80
n=10
n=10
n=8
50 2 0.4
n=7
*
100
* * 5
n=7
50 0.5
100 40
n=7
0.2
0 0 0 0 0 0 0 0 0
Time (min) 15 30 60 120 Time (min) 15 30 60 120
Fig. 2. Taurine supplementation increases health span in aged mice. (A to body weight per day) beginning at middle age (14 months). In (C), histology
K) Changes in body weight (A), fat percentage (B), bone structure, strength (left) and mCT (right) images are shown. A statistical analysis was performed using
parameters in spine and femur [(C) and (D)], neuromuscular and muscle strength Graph Pad Prism 7. Data were considered statistically significant at p ≤ 0.05
[(E) and (F)] (rotarod, wire hang, and grip-strength tests), anxiety (G) (tail calculated by using Student’s t test, one-way analysis of variance (ANOVA), or two-
suspension and dark-light tests), memory (H) (Y maze test), pancreas function way ANOVA. n values are shown within the panels. All values are means ± SEM.
(I) (glucose and insulin tolerance tests), GI transit (J) (oral carmine dye test), and ns indicates not significant. **p ≤ 0.01, and *p ≤ 0.05 are versus WT or control.
immunophenotyping (K) (immune cell parameters in blood) in 24-month-old WT BV, bone volume; BW, body weight; GTT, glucose tolerance test; ITT, insulin
C57Bl/6J female mice orally fed once daily with taurine (0, 500, or 1000 mg per kg tolerance test; TV, total volume.

Increased muscle endurance, coordination, Improved health-span metrics in middle-aged which encode inhibitors of cyclin-dependent
and strength in taurine-treated female mice male WT mice after taurine administration kinases and promote cell cycle arrest, formed
An analysis of the effect of taurine treatment To assess whether taurine affects the health the highest number of genetic interactions
on neuromuscular functions showed that total span of male mice, as it does in female mice, (fig. S4O). Consistent with the idea that tau-
hanging time and distance run in the rotarod we treated 14-month-old WT male mice with rine suppresses senescence, irradiation-induced
test was increased in the T500 and T1000 or without T1000 for 8 to 16 weeks and mea- increase in senescence-associated b-galactosidase
groups, whereas latency to fall in the wire hang sured fat, bone, muscle, pancreas, and brain (SΑ b-gal) staining in osteoblasts cultured with
test was increased in the T1000 group (Fig. 2E). health (fig. S3A). Taurine did not affect body- taurine was about one-fourth of that in cells
Grip strength tests revealed that both doses of weight gain in males up to 16 weeks but sig- cultured without taurine (fig. S4P). In neuronal
taurine increased muscle strength compared nificantly reduced fat-pad weight divided by culture experiments, taurine supplementation
with controls (Fig. 2F). body weight percentage compared to controls increased neuronal survival after treatment with
(fig. S3, B and C). To identify the cause of the paraquat, a DNA damaging agent that induces
Reduced depression-like behavior and reduced adiposity of taurine-treated mice, we senescence (49) (fig. S4Q). Moreover, taurine
anxiety and enhanced exploratory behavior analyzed energy expenditure. Taurine-treated supplementation decreased an age-associated
and memory in taurine-treated female mice mice consumed more oxygen, generated more increase in senescence in mice (Fig. 3, B and C,
Increased anxiety and decreased exploration carbon dioxide, and had higher respiratory and fig. S5A). To test whether taurine deficiency
are common age-induced behavioral changes exchange ratios and energy expenditures even causes accumulation of senescent cells, we used
(41). In the tail suspension test (42), taurine- though their total activity was decreased com- mice lacking the taurine transporter Slc6a6
treated mice showed less depression-like be- pared with that of controls (fig. S3, D to H). (23). Lack of Slc6a6 compromises taurine en-
havior compared with controls (Fig. 2G). The Taurine-treated male mice also showed greater try into embryonic cells, rendering embryos
light-dark box test (43) revealed that taurine- muscle strength, neuromuscular coordination, deficient in taurine. The phenotypes observed
treated mice spent less time in the dark area, bone density, glucose tolerance, and memory postnatally in 0.5- to 3-month-old Slc6a6 mu-
which is indicative of lesser anxiety (Fig. 2G). as well as reduced anxiety compared with con- tant mice (23) could be due to taurine deficiency
The Y maze test (44) showed that taurine-treated trols (fig. S3, I to N). Thus, taurine supplemen- affecting these phenotypes during development
mice had a higher natural curiosity for explo- tation improved the function of every organ or postnatally (hereafter, we refer to these
ration compared with control mice (Fig. 2H). investigated in middle-aged female and male mice as congenitally taurine-deficient mice).
mice and likely increased overall health span. Adult Slc6a6−/− mice showed accelerated aging-
Improved glucose homeostasis and related phenotypes, including decreased bone
gastrointestinal transit time in Effects of taurine on cellular mechanisms in density, poor neuromuscular coordination,
taurine-treated female mice increasing healthy life span compromised muscle strength, increased anxiety,
Analysis of glucose homeostasis using an in- What are the mechanisms through which tau- and decreased memory (fig. S5, C to L). Analy-
traperitoneal glucose tolerance test showed that rine affects cellular functions to increase healthy sis of bone, muscle, brain, fat, and liver showed
taurine-treated mice metabolized oral glucose life span? To address this question, we per- increased senescence in taurine-deficient mice
more efficiently than control mice and had lower formed an RNA-sequencing (RNA-seq) analy- compared with controls (fig. S5, A and B). To
glucose concentrations when fed ad libitum (Fig. sis in taurine-deficient and control osteoblasts investigate whether accumulation of senescent
2I). Likewise, taurine-treated mice had improved from mice. These bone-forming cells were cells in these organs contributes to the com-
insulin sensitivity in the insulin tolerance test chosen because they abundantly express a tau- promised health span of taurine-deficient mice,
(Fig. 2I). These improvements in glucose ho- rine transporter (encoded by Slc6a6), whose we treated 8-month-old Slc6a6−/− mice with or
meostasis might be a consequence of the reduced deletion impairs differentiation and function without a combination of senolytics—dasatinib
adiposity in taurine-treated mice. Gastrointes- of mutant cells in culture and in mice (fig. S4, (D) (50) and quercetin (Q) (D+Q treatment)—
tinal (GI) transit time increases with age (45). A to E). Conversely, numbers and function of bimonthly for 4 months. Relative to controls,
An analysis of intestinal transit time using non- WT osteoblasts were increased by taurine treat- D+Q-treated Slc6a6−/− mice had a lower abun-
absorbable red carmine dye administered by oral ment in vitro and in vivo. (fig. S4, A to E). dance of SASP markers (fig. S5M). D+Q treat-
gavage (46) showed a faster transit in taurine- RNA-seq analysis (48) of taurine-deficient os- ment also improved bone-, muscle-, anxiety-,
treated mice, which could contribute to the teoblasts showed that the top biological func- and memory-related parameters in Slc6a6−/−
observed weight loss in these mice (Fig. 2J). tions identified in the gene-set enrichment mice (fig. S5, N to Q). Taurine-deficient mice
analysis (GSEA) are related to aging mecha- had shorter lives than WT mice, and the me-
Ameliorated myeloid-leukocyte prominence nisms (13) such as telomere function, oxidative dian life span of mutant mice that received
in taurine-treated aged female mice stress, immune system function, protein trans- senolytic treatment until the end of life in-
Aging alters immune cell numbers in the lation, and stem cell maintenance (Fig. 3A creased by ~21% (Fig. 3D). The finding that
blood, resulting in increased susceptibility to and figs. S4, F to M). A search for the term senolytic treatment did not rescue the shorter
infection (47). A complete blood count showed “aging” in the GSEA pathways output showed life span of taurine-deficient mice suggests that
that taurine treatment decreased the number significant alterations in six gene signatures (see taurine also affects other factors besides senes-
of white blood cells (WBCs), monocytes, and table S1 for details). All six signatures showed cence. We therefore assessed molecular and
granulocytes but not the number of red blood the expected direction of change (up- or down- cellular features of other aging hallmarks in
cells (Fig. 2K and fig. S2H). Although there regulation) for a pro-aging effect (fig. S4N). taurine-supplemented middle-aged mice and
was no difference in the efficacy of T500 and Together, these results imply that taurine de- in taurine-deficient mice.
T1000 doses on the WBC numbers, the num- ficiency generates an aging-related transcrip-
bers of monocytes and granulocytes were only tomic signature in cells. Taurine suppresses adverse consequences
decreased at the T1000 dose (Fig. 2K). These of telomerase deficiency
results show that the myeloid-leukocyte prom- Suppression of senescence by taurine Replication-based telomere shortening triggers
inence associated with aging-related inflamma- A network analysis of taurine-regulated genes cellular senescence and affects aging (51). Tau-
tory states is ameliorated by high-dose taurine showed that senescence-associated secretory rine supplementation in mice or zebrafish or
treatment. phenotype (SASP) genes, such as p16 and p21, its deficiency in mice did not affect telomerase

A Taurine regulated transcriptome B SA- -Gal C D WT + Veh E

+ Slc6a6-/- (Veh)***
n=3, each group Slc6a6-/- (Senolytics)**
Aging hallmarks
Brain
Telomere shortening 100
Fold change in senescence

1 tert+/+
Altered Cell-cell communication
Survival (%)
SA- -Gal
Cellular senescence
* * * tert-/-
Liver
Deregulated nutrient sensing 50
Epigenetic changes
* * tert-/- (300 m)
Genomic instability
Loss of proteostasis n>20, each group
0 tert-/- (10mM)
Fat
Mitochondrial dysfunction 0 15 19 23 27 31 34 37
n=4, each group
e
r
ut
t
ve
Age (months)
ai
cl
Fa
G
us
Br
Stem cell exhaustion
Li
M
n=3, each group
F n=4
G H * I J K + Taurine
n=10
3 H3K27me3
Serum 8OH-dG levels (ng/mL)

100 100
Liver
1 H3K9me3
2
SA -Gal intensity
n=10
H3
Survival (%)
0.5
Survival (%)
Skeletal Muscle
2
Cerebral cortex
H3K27me3
Brown fat
0
Liver
50 tert+/+ (n=55) 50 H3K9me3
n=4 n=4 1 Veh (n=10)
tert-/- (n=47)
**
-0.5
1 PQ (n=12)*** H3
tert-/- (300 m) (n=46)
tert-/- (10mM)**(n=47)
PQ + Taurine (n=10)*** -1
H3K27me3
Muscle
n=4
0 0 0 0 H3K9me3
0 24 48 72 96 120 136 168
Taurine 0 5 10 + H3
M
A Y AT A Y AT Y A AT
M
m
Time (hours) post PQ

0
Days post fertilization Taurine

10
30
tert+/+ tert-/- ns
L + + + Taurine M *
N *
O P6 WT (Veh) Q Young * *
ns
6 **
pRS6P * 180 ** 80 * ** Slc6a6-/- (Veh) Aged (Veh)
* *
Slc6a6-/- (Rapa) Aged (Taurine)
RS6P *
Serum levels (pg/mL)

n>5, each group
Grip Strength (g/g)
* *
Alterations (%)
n>5, each group

Immobility (sec)
GAPDH 4 4 100
BV/TV%
120 ns
40
*
LC3A/B
2 60
2 * * *
ns
ns
**
GAPDH
**
Brown Fat Liver Muscle 0
R + Taurine
0 0 0 0 TNF IL17 KC EO RANTES IL1 GM-CSF MCP-1
S T U V W X Y
Taurine
Gut
* * * Y A AT TNF
* Taurine
* Aging hallmarks?
Slc6a6 IL17
Lgr5
(MitoSOX, relative to controls)
Nd6
Protein carbonylation (nmol/mg)
n=10
RANTES
n=10
+
Reactive oxygen specieis
IL1
Lipid peroxidation (nmol/ g)
1.0 tRNALeu
m5U-tRNA (fold change)
1.0 1.0 Cysteine
*
n=10
Mto1 Osmosensor GM-CSF

n=10
Pgc1 Isethionic acid

1 m5UAA
n=10
N-Acetyl taurine Cytokine

Gtpbp3 Bile acids
H2S receptors
Ucp1 ND6 translation
Skin GAPDH
Stem cell renewal Complex I
0.5 0.5
Ucp2
n=10
RS6P ROS
Lgr5
GAPDH Autophagy N-Chlorotaurine

DNA damage Telomere attrition
Proteostasis Inflammaging
Brown fat
0.0 0.0 0 0
A AT A AT A AT Y A AT Epigenetic changes Intercellular communication
Nutrient sensing Senescence
Fig. 3. Taurine regulation of healthy life span is associated with alterations P) Changes in muscle function (grip-strength test) (M), anxiety (tail suspension
in multiple aging hallmarks. (A) Circos plot representing a comparative test) (N), memory (Y maze test) (O), and bone mass [bone volume divided by
analysis of a taurine-deficient transcriptome with the core gene signatures of total volume percentage (BV/TV%)] (P) in 6-month-old Slc6a6−/− mice and
nine aging hallmarks. (B and C) SA b-Gal staining (blue-stained cells) (B) and littermate controls that received either vehicle or rapamycin (once daily for
relative quantification of staining (C) in tissues collected from mice with or 6 weeks). (Q) Serum levels of various cytokines in young mice, aged mice, and
without taurine supplementation, as viewed with whole-mount imaging. (D) Life- aged mice treated with taurine. EO, eotaxin; KC, keratinocyte cytokine. (R to V) In
span assay of congenitally taurine-deficient (Slc6a6−/−) mice and littermate situ hybridization analysis of Lgr5 expression in the gut and skin (R), levels of
controls that received either vehicle or senolytics (D+Q treatment) biweekly until mitochondrial ROS (superoxide anion radicals, MitoSOX assay) in skeletal muscle
the end of life. (E to G) SA b-Gal staining photomicrographs (E), relative mitochondria (S), protein carbonyl levels in the liver (T), lipid peroxidation levels
quantification of staining (F), and survival analysis (G) of telomerase-deficient in the liver (U), and Pgc1a, Ucp1, and Ucp2 levels in the brown fat (V) of aged
[tert−/−(G2)] zebrafish embryos with or without taurine supplementation mice treated without or with taurine. (W and X) Changes in tm5U tRNA
(300 mm or 10 mM) beginning at 2 dpf. (H) Serum 8-OH-dG concentrations modification (W) and Nd6, Mto1, and Gtpbp3 protein levels in the liver (X) of young
in vehicle-treated (−) or taurine-treated (+) mice. (I) Kaplan-Meier survival mice, aged mice, and aged mice treated with taurine. In (W), n ≥ 6 mice in
curves for mice after paraquat (PQ) treatment, with or without prior taurine each group. (Y) Schematic representation of the effect of taurine and taurine-
supplementation (T1000 for 1 month). Veh, vehicle. (J and K) Comparative derived biomolecules (in red) on classical hallmarks of aging. For (K), (L), (V), and
DNA methylation levels of 2045 age-related CpG sites in the muscle, cerebral (X), Western blots are representative of at least three independent biological
cortex, and liver (J) and changes in histone H3K27me3, H3K9me3, and H3 levels replicates. Statistical analysis details are as follows: For (D), (G), and (I), the OASIS
in the liver, brown fat, and muscle (K) of 4-month-old WT (young, Y), 16-month- software (https://sbi.postech.ac.kr/oasis) was used to calculate p values using
old vehicle-treated WT (aged, A), and 16-month-old taurine-treated WT (aged- a log rank test (the Mantel-Cox method), and for other panels, statistical analysis
taurine, AT) mice. (L) Changes in phosphoribosomal S6 protein (pRS6P) was performed with Graph Pad Prism 7 using Student’s t test or one-way or
and LC3A/B levels in the brown fat, liver, and muscle of vehicle- or taurine- two-way ANOVA. All values are means ± SEM. ns indicates not significant. ***p ≤
treated aged mice. GAPDH, glyceraldehyde phosphate dehydrogenase. (M to 0.001, **p ≤ 0.01, and *p ≤ 0.05 are versus WT or control.

gene expression (fig. S5, R and S). To inves- abundance was suppressed in the liver, Positive effects of taurine on the health of
tigate whether taurine affects telomerase increased in muscle, and unaffected in brown stem cells or their renewal
deficiency–induced deterioration in organismal fat (Fig. 3K). The varied changes in DNA and Aging reduces the ability of tissues to regen-
health, we used a zebrafish model of telome- histone methylation indicate that taurine erate after injury. This is linked to defects in
rase deficiency (52). tert−/−(G2) fish show an may affect chromatin conformation, which tissue-specific stem cells (60). We analyzed
increase in senescence, and ~40% of them die could contribute to altered transcription dur- changes in the number of stem cell popula-
within 10 days postfertilization (dpf) (52). Sup- ing aging. tions in the gut epithelium and hair follicles
plementing the medium used for tert−/−(G2) obtained from untreated and taurine-treated
fish with taurine, starting at 2 dpf, suppressed Taurine modulates nutrient sensing and middle-aged mice through staining for the
senescence (Fig. 3, E and F). Moreover, at con- proteostasis pathways gene encoding leucine-rich repeat–containing
centrations of 300 mM and 10 mM, taurine res- Aging cells have a reduced ability to sense G protein–coupled receptor 5 (Lgr5), which
cued lethality in tert−/−(G2) zebrafish embryos nutrients and maintain proteostasis (57). We is a wingless-related integration site (Wnt) tar-
(Fig. 3G). assessed changes in nutrient sensing by mea- get gene expressed in the stem or progenitor
suring the phosphorylation of ribosomal S6 cells (61). The numbers of Lgr5+ cells in these
Taurine suppresses DNA damage and protein (RS6P), a key regulator of ribosomal two tissues were increased by taurine supple-
improves the survival of mice after function, and proteostasis by measuring changes mentation (Fig. 3R). Conversely, the numbers
oxidative DNA damage in abundance ratio of isoforms A and B of the of Lgr5+ cells in the gut epithelium and hair
Aging is associated with genomic DNA lesions light chain 3 (LC3A/B), an autophagy marker. follicles were decreased in taurine-deficient
in multiple cell types (53). Taurine supplemen- Taurine supplementation decreased phospho- mice compared with control mice (fig. S5W).
tation reduced serum 8-hydroxydeoxyguanosine rylation of RS6P in the liver, brown fat, and Thus, taurine supplementation may increase
(8-OH-dG) abundance, a measure of oxidative skeletal muscle (Fig. 3L). Phosphorylation of the regenerative capacity of some tissues by
DNA damage (54), in aged mice (Fig. 3H). RS6P was increased in the muscle of taurine- increasing the number of resident stem cells.
Conversely, DNA damage [measured as the deficient mice (fig. S5V). Taurine-supplemented
abundance of phospho-g-H2A histone family mice had more autophagy (as judged by LC3A/B Taurine promotion of mitochondrial health
member X (H2Ax)] was increased in the mus- abundance) in the liver, brown fat, and skeletal Compromised mitochondrial biogenesis and
cle of taurine-deficient mice (fig. S5T). In a muscle, whereas it was decreased in taurine- oxidative capacity leads to progressive accu-
paraquat model of DNA damage–induced deficient mice (Fig. 3L and fig. S5V). To test mulation of reactive oxygen species (ROS)–
lethality, mice administered with paraquat whether an increase in phosphorylation of RS6P mediated damage that contributes to aging
without prior taurine supplementation died and a decrease in autophagy contribute to the (62). ROS accumulation in mitochondria iso-
within 150 hours, but mice treated with tau- compromised health span in taurine-deficient lated from the muscle of taurine-treated middle-
rine lived slightly longer (Fig. 3I). Thus, taurine mice, we treated Slc6a6−/− mice with or with- aged mice was decreased compared with that
supplementation suppressed DNA damage and out rapamycin [8 mg per kg body weight in the muscle of control mice (Fig. 3S), whereas
improved the survival of mice after oxidative intraperitoneally once daily (58) for 6 weeks], it was increased in the muscle of taurine-
DNA damage. which inhibits phosphorylation of RS6P and deficient mice (fig. S6A). Measurement of lipid
increases autophagy. Compared with control peroxidation and protein carbonylation, two
Taurine affects epigenetic changes mice, rapamycin-treated taurine-deficient indirect markers of ROS-induced molecular
in the genome mice showed improved muscle-, anxiety-, and damage, in the liver showed a decrease (of ~22
Methylation at CpG sites and of histones changes memory-related parameters but not increased and ~11%, respectively) in taurine-supplemented
with age and affects the state of chromatin, bone mass (Fig. 3, M to P). Thus, the effects of mice compared with control mice (Fig. 3, T
which affects DNA packaging and gene expres- taurine supplementation on nutrient sensing and U). Assessment of the abundance of per-
sion (55, 56). We therefore analyzed changes in and proteostasis pathways contribute to its oxisome proliferator–activated receptor–gamma
methylation of 2045 CpG sites and measured beneficial effects on several health parameters. coactivator 1 alpha (Pgc1a), a key regulator of
two histone modifications [histone 3 lysine 9 mitochondrial biogenesis, and uncoupling pro-
trimethylation (H3K9me3) and histone 3 lysine Taurine effects on inflammatory cytokines tein 1 (Ucp1), which uncouples mitochondrial
27 trimethylation (H3K27me3)] in multiple tis- Intercellular communication is compromised fuel oxidation and respiration from adenosine
sues obtained from untreated or taurine-treated with age (59). One example is the accumula- triphosphate (ATP) production (63), in brown
middle-aged mice and compared them with tion of proinflammatory and other cytokines fat showed increased amounts in taurine-treated
those in tissues from young mice. Clustering (59). Serum concentrations of tumor necro- middle-aged mice, and their abundance was
analysis showed that the CpG methylation sis factor–a (TNFa), interleukin-17a (IL-17a), decreased in taurine-deficient mice (Fig. 3V and
pattern in the muscle and cerebral cortex of RANTES (regulated upon activation, normal fig. S6B). These results indicate that taurine
taurine-treated old mice was more similar to T cell expressed and presumably secreted), promotion of mitochondrial homeostasis may
that in young mice than to that in untreated IL-1a, and granulocyte-macrophage colony- contribute to its effect on health.
old mice (Fig. 3J). However, the pattern in stimulating factor (GM-CSF) were increased We next investigated how taurine affects
liver from taurine-supplemented mice was in middle-aged mice compared with young cellular mechanisms during aging (24). One
more similar to that in old mice than to that mice, but taurine-treated middle-aged mice pool of cytosolic taurine is actively transported
in young mice (Fig. 3J). Conversely, muscles had amounts of these cytokines that were sim- into mitochondria, where it is conjugated to
from taurine-deficient mice showed changes ilar to those in young control animals (Fig. the uridine residue at the wobble position of
in the amount of CpG site methylation, and 3Q). These results, together with the observa- tRNALeu(UUA), forming 5-taurinomethyluridine-
the DNA methylation pattern of muscles in tion that the ratio of myeloid cells to lymphoid tRNALeu(UUA) (tm5U-tRNA) (64). tm5U mod-
70-week-old taurine-deficient mice was sim- cells was significantly decreased in taurine- ification is specific to mitochondrial tRNAs
ilar to that in 206-week-old WT mice (fig. supplemented mice (Fig. 2K), indicates that (64) and promotes the translation of NADH-
S5U). Taurine treatment decreased the abun- sustained taurine concentrations help prevent ubiquinone oxidoreductase chain 6 protein
dance of H3K9me3 in brown fat and liver but the proinflammatory state that is observed (ND6), an electron transport chain complex I
increased it in skeletal muscle; H3K27me3 during aging. subunit (64). We therefore measured whether

tm5U tRNA modification changed during ag- ercise, which improves many health- and by ~36 and 20%, respectively (Fig. 4, H and I).
ing in mice. The tm5U content of tRNAs was aging-related variables (67, 68). Specifically, we Numbers of WBCs, monocytes, and granulo-
reduced by >60% in aged liver compared with analyzed concentrations of taurine-pathway cytes, which increase with age, were decreased
young liver; in taurine-supplemented mice, the metabolites in serum before and after a graded by ~50% in taurine-treated monkeys com-
tm5U content of tRNAs was reduced by only exercise test in male athletes (sprinters, endu- pared with control monkeys (Fig. 4, J to L).
about 20% (Fig. 3W and fig. S6C). Consistent rance runners, and natural bodybuilders) and Consistent with the beneficial effect of taurine
with the role of tm5U-tRNALeu in promoting sedentary individuals (fig. S7C). Taurine levels on the mitochondrial health observed in worms
the translation of ND6, amounts of this pro- significantly increased (1.16-fold) in response and mice, indirect markers of ROS-induced
tein were decreased in aged mice compared with to a graded cycle exercise test in all the inves- molecular damage—DNA 8OH-dG, lipid per-
young mice and were increased by taurine tigated athlete groups (pbodybuilding = 0.046, oxide, and protein carbonyl concentrations—
supplementation (Fig. 3X and fig. S6D). Taurine pendurance = 0.0021, psprint = 0.0017) (Fig. 4B) were decreased by ~36, 11, and 20%, respec-
supplementation, however, did not affect the and tended to be higher in the sedentary sub- tively, in the sera of taurine-supplemented
translation of nuclear DNA–encoded mitochon- jects, although the change was not significant monkeys (Fig. 4, M to O). Thus, taurine has
drial oxidative phosphorylation (OXPHOS) (psedentary = 0.067) (Fig. 4B). Levels of hypo- beneficial effects on most tested health param-
proteins in aged mice (fig. S6E). We conducted taurine were significantly increased 1.36-fold eters (body weight, bone, glucose, liver, and
experiments on worms to test whether regula- in response to exercise in all subjects (Fig. 4C). immunophenotype) in nonhuman primates.
tion of organismal health by taurine requires Levels of N-acetyltaurine were significantly
complex I activity. Taurine increased the motility increased by 1.18- and 1.28-fold in endurance Discussion
of control worms, which is indicative of better athletes (p = 0.027) and sprinters (p = 0.0016), Taurine abundance decreases in blood and
health status (65), but failed to do so in rotenone- respectively, and tended to be elevated in body- tissues during aging. We found that a reversal
treated worms (fig. S6F), suggesting that in- builders and sedentary subjects, although the of this decline through taurine supplementa-
creasing mitochondrial complex I activity is a change was not significant (pbodybuilders = 0.054, tion increased markers of healthy life span in
mechanism by which taurine promotes health. psedentary = 0.067) (Fig. 4D). These results are worms and mice as well as health span in
The aforementioned analyses of molecular and consistent with the notion that an increase in monkeys, which identifies taurine deficiency
cellular features of aging hallmarks show that taurine and taurine-related metabolites might as a driver of aging in these species. In mice,
during aging, taurine supplementation may mediate some of the health benefits of exercise. the effect of taurine supplementation on
impart health benefits by affecting such features healthy life span was greater in females than
in various cells or tissues (Fig. 3Y). Taurine supplementation improves health in males, indicating that sex-specific pathways
parameters in middle-aged nonhuman primates may mediate taurine action. The optimal dose
Lower circulating taurine and its metabolites To test whether taurine has health and anti- of taurine to maximize its efficacy differed de-
in humans are associated with multiple aging effects in nonhuman primates, we fed pending on the physiological functions tested,
age-associated pathologies aged rhesus monkeys (15 ± 1.5 years old, equiv- which was possibly due to a wide variation in
To determine whether blood levels of taurine- alent to 45 to 50 years old in humans) control the uptake rate, synthesis, and metabolism of
pathway metabolites (taurine, hypotaurine, and solution or taurine [250 mg per kg body weight taurine in different biological fluids and tis-
N-acetyltaurine) are associated with health var- (T250), equivalent to T1000 in mice] at 10:00 am sues (24, 69–76).
iables in humans, we performed an association once daily for 6 months and then measured Taurine appeared to affect all the established
analysis of circulating taurine metabolite levels the health variables (fig. S7D). Before the start hallmarks of aging. Although we do not yet
with >50 clinical risk factors in 11,966 subjects of taurine supplementation, body weight and know the initial events that taurine elicits, we
of the EPIC-Norfolk study (fig. S7, A and B) (66). bone density were not significantly different provide evidence for the suppressed tauriny-
We found that higher blood taurine and hypo- in the two groups of aged monkeys (fig. S7, E lation of mitochondrial tRNAs during aging in
taurine levels were associated with lower body and F). Three hours after oral feeding, serum mitochondrial dysfunction, a prominent fea-
mass index (BMI) and waist-to-hip ratio as well taurine concentrations in taurine-fed monkeys ture of aging. It is also possible that other
as less abdominal obesity (Fig. 4A). Further- were about twice (65.4 ± 10.1 ng/ml) that in taurine-derived biomolecules besides tm5U-
more, higher levels of taurine metabolites were controls (35.1 ± 7.3 ng/ml). Monkeys that re- tRNA may directly or indirectly affect mito-
associated with a lower prevalence of type 2 ceived taurine gained 0.75 kg less body weight, chondrial homeostasis or other aging features.
diabetes and lower glucose levels (Fig. 4A). and their fat percentage tended to be lower Indeed, taurine contributes to the production
Also, higher taurine and hypotaurine levels were compared with that of controls (Fig. 4E). In- of several other biomolecules, depending on
associated with lower levels of the inflammation life dual-energy x-ray absorptiometry (DEXA) the cell type or types that affect, or can po-
marker C-reactive protein (CRP). For liver- and analysis after 6 months of taurine treatment tentially affect, aging (24). These molecules
lipid-related traits such as aspartate aminotrans- showed that taurine increased bone density include N-chlorotaurine (77), hydrogen sulfide
ferase (AST) and blood cholesterol, we found and content in the lumbar spine (L1 to L4) (H2S) (78), isethionic acid (24), N-acetyltaurine
positive associations with taurine levels but and legs, but not in the head, in taurine-treated (79), and 5-taurinomethyl-2-thiouridine (tm5s2U)-
negative associations with those of its precur- monkeys compared with control monkeys tRNALys (24). We propose that a combination
sor hypotaurine (Fig. 4A). Blood cell parameters (Fig. 4F and fig. S7, G and H). Serum markers of taurine and taurine-derived biomolecules
like hemoglobin, platelets, and WBC count cor- of bone formation (osteocalcin) increased, may delay aging by affecting various aging
related positively with the three taurine metab- whereas those of resorption [C-terminal telo- hallmarks in distinct cells and tissues.
olites (Fig. 4A). Association does not establish peptide of type 1 collagen (Ctx)] decreased The effects of taurine intervention on aging
causation, but these results are consistent with about 16 weeks after the start of treatment; and congenital taurine deficiency in a mouse
taurine deficiency contributing to human aging. these levels were maintained until the end of model are largely consistent, except for body
the dosing period (fig. S7, I and J). Taurine weight accrual and glucose homeostasis (Fig. 2
A bout of exercise increases abundance of treatment reduced fasting blood glucose con- and fig. S5). The concentrations of taurine in
taurine and its metabolites centrations by 19% (Fig. 4G). Taurine also re- the serum and tissues of congenitally taurine-
We next investigated whether blood levels of duced the serum concentrations of liver damage deficient mice are more severely reduced than
taurine-pathway metabolites respond to ex- markers AST and alanine transaminase (ALT) in the biological fluids and tissues of aged

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Taurine *** *** ** *** *** *** *** *** *** *** *** ** *** *** *** *** *** *** ** *** *** ***
0.0
Hypotaurine *** *** *** *** * *** *** *** ** *** *** *** *** *** *** *** *** *** *** *** 0.3
11,966 subjects N−acetyltaurine * *** *** *** ** *** *** ** *** *** ** * * *** *** *** *** *** 0.6
B C D
Baseline Taurine Hypotaurine N-acetyltaurine
*** * **
Post-exercise * ***
p=0.067 p=0.054 Sedentary subjects
p=0.067 2
* **
Metabolite level (scaled)
** ***
2 2
Natural body builders

0 0 0
-2
-2
-2 Endurance athletes
Sprinters
Vehicle
T250 mg/kg BW/day
E Macaca mulatta
F * G H I J K L M N O
* L1-4
* * * *
Protein carbonylation (nmol/mg)

15 0.8 15
1 p=0.10
* * 0.6
*
Serum 8OH-dG levels (ng/mL)

Fasting glucose levels (mg/dL)
Bone Mineral Density (g/cm2)
Body weight gain (in Kg)
Lipid peroxidation (nmol/ g)

* *
Granulocytes (X106/mm3)
*
Bone Mineral Content (g)
100 30 20 5.0
n=5
Serum ALT levels (IU/L)
n=5
5.0 1.50
Serum AST levels (IU/L)
n=5
Monocytes (X106/mm3)
n=5
n=5
12 5.0
WBC (X106/mm3)
n=5
0.6
n=6
n=5
n=5
10 0.4
n=5
n=5
n=5
n=5
% Fat gain
n=5
n=6
n=6
n=6
0.5 7.5 0.4 8

n=5
50 15 10 2.5 2.5 0.75 2.5
n=6
n=6
5
n=5
n=6
0.2
n=6
0.2 4
n=6
0 0 0 0 0 0 0 0 0 0 0 0.00 0.0
Fig. 4. Taurine pathway affects health span in primates. (A) Heatmap relative to the mean of measured levels with mean = 0 and standard deviation = 1.
showing the results from linear regression models for assessing the associations (E to O) Body-weight gain in kilograms and percent fat gain (E); bone mineral
between clinical risk factors and taurine-related metabolites (taurine, hypotaur- density and content in the lumbar spine (L1 to L4) (bone) (F); fasting glucose
ine, and N-acetyltaurine) in blood from 11,966 subjects in the EPIC-Norfolk study. levels (pancreas function) (G); serum AST and ALT levels (liver dysfunction
Effect size and direction of these associations are given by the b estimates markers) [(H) and (I)]; WBC, monocyte, and granulocyte numbers (immuno-
resulting from these regression models. A negative b estimate (blue color) phenotyping in blood) [(J) to (L)]; and serum 8-OH-dG, lipid peroxide, and
indicates an inverse association, where higher levels of a metabolite correlated protein carbonyl levels (indirect markers of ROS-induced molecular damages)
with lower levels of a clinical parameter. A positive b estimate (red color) [(M) to (O)] in 15-year-old monkeys orally fed once daily with vehicle (T0) or
indicates a positive association, where higher levels of a metabolite correlated taurine (T250) for 6 months. Statistical analysis details are as follows: For (A),
with higher levels of a clinical parameter. For example, as shown in blue, summary statistics, including standardized regression coefficients (b estimates)
higher levels of taurine correlated with a lower prevalence of type 2 diabetes. and nominal p values, on a relevant subset of 26 clinical traits and three taurine-
Taurine-related metabolites were measured using an untargeted metabolomics related metabolites were extracted from a web server. Regression coefficients
approach (Metabolon HD4 platform). Data were extracted from the open- and nominal p values were plotted in a heatmap using R version 4.1.0. For
access web server located at https://omicscience.org/apps/mwasdisease/. the exercise cohort in [(B) to (D)], differences between baseline and postexercise
AP, alkaline phosphatase; APOB, apolipoprotein B; eGFR, estimated glomerular metabolite levels were analyzed per subject group using a paired-sample t test.
filtration rate; GGT, g-glutamyl transferase; HB, hemoglobin; LDL, low-density Batch corrections were done using R version 4.1.0; the graphs were prepared
lipoprotein; WHR, waist-to-hip ratio. (B to D) Serum taurine (B), hypotaurine (C), using GraphPad Prism. For [(E) to (O)], statistical analysis was performed
and N-acetyltaurine (D) levels at fasted rest (baseline) and 5 min after a maximum with Graph Pad Prism 7 using Student’s t test or one-way or two-way ANOVA.
graded exercise test (postexercise) in three groups of competitive athletes and All values are means ± SEM. p ≤ 0.001***, p ≤ 0.01**, and p ≤ 0.05* are versus
healthy sedentary subjects. Metabolite levels are provided as z-scores, that is, WT or control.
rodents and humans (23, 27, 80). However, in adult tissues; moreover, taurine deficiency tabolism might affect the rate of aging during
the liver, the concentrations of tm5U, a down- during development leads to growth retarda- late life, and adjusting this endogenous machin-
stream conjugate of taurine, were similarly af- tion, blindness, and osteoporosis (25, 81), and ery might extend healthy life span.
fected. Thus, during early life, taurine appears its supplementation during gestation increased In humans, lower levels of taurine-pathway
to be essential for homeostasis in several or- bone mass postnatally (fig. S5X). This role of metabolites were associated with multiple age-
gan systems, and its deficiency during devel- taurine in embryonic tissues that affects post- associated diseases, such as obesity, diabetes,
opment may compromise these functions natal phenotypes would be consistent with the and inflammation (Fig. 4A). In the FinnGen
postnatally. Consistent with this hypothesis, theory of the developmental origin of aging database (Freeze R5), polymorphisms in the
organisms have a three- to fourfold higher tau- phenotypes (82, 83). It is possible that devel- taurine biosynthesis gene, CSAD, are associ-
rine concentration in embryonic tissues than in opmental or postnatal changes in taurine me- ated with hypertension (fig. S7K), and SLC6A6

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Writing – review and editing: V.K.Y., H.W., M.A.Y., B.P., G.K., M.K., License information: Copyright © 2023 the authors, some Figs. S1 to S7
D.S., A.M., P.S., M.C., K.G., S.M. Competing interests: Columbia rights reserved; exclusive licensee American Association for the Table S1
University has filed provisional patent applications on which V.K.Y. Advancement of Science. No claim to original US government References (89–130)
is listed as an inventor. The remaining authors declare works. https://www.sciencemag.org/about/science-licenses- MDAR Reproducibility Checklist
no competing interests. Data and materials availability: All journal-article-reuse
data are available in the main text or the supplementary materials. View/request a protocol for this paper from Bio-protocol.
The codes used for data analysis are stored publicly at github
main_taurine.R at https://github.com/stemangiola/ SUPPLEMENTARY MATERIALS Submitted 1 January 2022; resubmitted 20 September 2022
singh_et_al_taurine_bone/blob/master/main_taurine.R. science.org/doi/10.1126/science.abn9257 Accepted 14 April 2023
Sequencing scaled counts have been deposited at Zenodo (88). Materials and Methods 10.1126/science.abn9257

Taurine deficiency as a driver of aging
Parminder Singh, Kishore Gollapalli, Stefano Mangiola, Daniela Schranner, Mohd Aslam Yusuf, Manish Chamoli, Sting L.
Shi, Bruno Lopes Bastos, Tripti Nair, Annett Riermeier, Elena M. Vayndorf, Judy Z. Wu, Aishwarya Nilakhe, Christina Q.
Nguyen, Michael Muir, Michael G. Kiflezghi, Anna Foulger, Alex Junker, Jack Devine, Kunal Sharan, Shankar J. Chinta,
Swati Rajput, Anand Rane, Philipp Baumert, Martin Schönfelder, Francescopaolo Iavarone, Giorgia di Lorenzo, Swati
Kumari, Alka Gupta, Rajesh Sarkar, Costerwell Khyriem, Amanpreet S. Chawla, Ankur Sharma, Nazan Sarper, Naibedya
Chattopadhyay, Bichitra K. Biswal, Carmine Settembre, Perumal Nagarajan, Kimara L. Targoff, Martin Picard, Sarika
Gupta, Vidya Velagapudi, Anthony T. Papenfuss, Alaattin Kaya, Miguel Godinho Ferreira, Brian K. Kennedy, Julie K.
Andersen, Gordon J. Lithgow, Abdullah Mahmood Ali, Arnab Mukhopadhyay, Aarno Palotie, Gabi Kastenmüller, Matt
Kaeberlein, Henning Wackerhage, Bhupinder Pal, and Vijay K. Yadav
Science, 380 (6649), eabn9257.

DOI: 10.1126/science.abn9257
Editor’s summary
Aging is associated with physiological changes that range in scale from organelles to organ systems, but we are still
working to understand the molecular basis for these changes. Studying various animals, Singh et al. found that the
amount of the semi-essential amino acid taurine in circulation decreased with age (see the Perspective by McGaunn
and Baur). Supplementation with taurine slowed key markers of aging such as increased DNA damage, telomerase
deficiency, impaired mitochondrial function, and cellular senescence. Loss of taurine in humans was associated with
aging-related diseases, and concentrations of taurine and its metabolites increased in response to exercise. Taurine
supplementation improved life span in mice and health span in monkeys. —L. Bryan Ray
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RES EARCH

◥ which taurine supplementation improved

High glucose Liver disease

Taurine Effects on aging hallmarks

Singh et al., Science 380, 1028 (2023) 9 June 2023 1 of 1

◥ a correction to its youthful levels would de-

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 1 of 11

Serum taurine ( mol/L)

Serum taurine (ng/ml)

Q6ZQY3 H. sapiens GADL1

P20228 D. melanogaster Gad1

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 2 of 11

0 0 Vertebra (BV/TV%) Femur (BV/TV%)

D Skeleton strength E Neuromuscular coordination F Grip strength G Anxiety H Memory

I Glucose homeostasis J GI Transit K Immunophenotype

T1000 (n=10) 120 T1000 (n=15)

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 3 of 11

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 4 of 11

A Taurine regulated transcriptome B SA- -Gal C D WT + Veh E

Fold change in senescence

Serum 8OH-dG levels (ng/mL)

Time (hours) post PQ

Days post fertilization Taurine

Serum levels (pg/mL)

n>5, each group

(MitoSOX, relative to controls)

1.0 1.0 Cysteine

Mto1 Osmosensor GM-CSF

Pgc1 Isethionic acid

N-Acetyl taurine Cytokine

GAPDH Autophagy N-Chlorotaurine

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 5 of 11

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 6 of 11

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Natural body builders

Protein carbonylation (nmol/mg)

Serum 8OH-dG levels (ng/mL)

Lipid peroxidation (nmol/ g)

Serum ALT levels (IU/L)

0.5 7.5 0.4 8

50 15 10 2.5 2.5 0.75 2.5

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 8 of 11

Singh et al., Science 380, eabn9257 (2023) 9 June 2023 9 of 11

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Science, 380 (6649), eabn9257.

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