Article

ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, No. 11, pp. 1732-1738 © Pleiades Publishing, Ltd., 2023.

Published in Russian in Biokhimiya, 2023, Vol. 88, No. 11, pp. 2101-2108.

1732

REVIEW

Potential Geroprotectors – From Bench to Clinic

A l e x e y A . M o s k a l e v

Institute of Biogerontology, Lobachevsky University, 603950 Nizhny Novgorod, Russia

e-mail: amoskalev@list.ru

Received July 20, 2023

Revised September 20, 2023

Accepted September 20, 2023

Abstract— Geroprotectors are substances that slow down aging process and can be used for prevention of age-related diseas-

es. Geroprotectors can improve functioning of various organ systems and enhance their homeostatic capabilities. We have

developed a system of criteria for geroprotectors and proposed their classification based on the mechanisms of their action

on the aging processes. Geroprotectors are required to reduce mortality, improve human aging biomarkers, have minimal

side effects, and enhance quality of life. Additionally, there are approaches based on combining geroprotectors targeted

to different targets and mechanisms of aging to achieve maximum effectiveness. Currently, numerous preclinical studies

are being conducted to identify new molecular targets and develop new approaches to extend healthy aging, although the

number of clinical trials is limited. Geroprotectors have the potential to become a new class of preventive medicines as they

prevent onset of certain diseases or slow down their progression.

DOI: 10.1134/S0006297923110056

Keywords: geroprotector, aging, biomarker, biological age, criteria

INTRODUCTION

Geroprotectors are compounds affecting the mech-

anisms of aging and slowing it down. They could be used

for prophylactics and delay of onset of age-related dis-

eases and extension of active period of life. Geroprotec-

tors could become and important part of modern pro-

phylactic and personalized medicine [1], and, first of all,

of the emerging medicine of healthy longevity [2].

Aging is the main cause of numerous age-related

diseases such as cardiovascular diseases, cancer, dia betes,

and neurodegenerative diseases. Studying of geroprotec-

tors could shed light on the main biological processes

underlying aging. This could help us to understand what

molecular and cellular changes occur in an organism

with aging, and what mechanisms could be modulated

to achieve geroprotection. Investigation of geroprotec-

tors could help us to develop strategies for preventing

or slowing down onset of these diseases. This is of tre-

mendous importance for improving quality of life of

individuals and to reduce economic burden on health-

care systems. However, it must be mentioned that inves-

tigation of geroprotectors is a complicated task. There

are multiple factors that could affect the results of such

studies, such as differences in experimental conditions,

genotypes and species of model organisms, problems

with short-lived controls, and irreproducibility of data.

This means that further studies and developments are

required to establish efficiency and safety of potential

geroprotectors for humans.

POTENTIAL GEROPROTECTORS

We have developed a set of criteria for geroprotec-

tors with the goal to describe to the fullest the desired

features and properties of a geroprotector and facilitate

its introduction into medical practice for prophylactics

of aging. We identified main criteria (ensuring effec-

tiveness and safety) and auxiliary criteria (accelerating

translation into practice) [3].

Main criteria for geroprotector. Geroprotector must

increase lifespan. Whether the substance is geroprotector

or not is judged by its ability to increase lifespan of the

model organism under the used experimental conditions

or decrease general human mortality. Our open on-line

database (geroprotectors.org) compiled based on 2408

literature sources includes 259 compounds that increase

lifespan at least at one concentration in one of 13 model

organisms from yeasts to humans [4]. Recently a data-

base within the framework of the DrugAge project was

created with our participation that includes more than

POTENTIAL GEROPROTECTORS 1733

BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023

1000 compounds effects of which on lifespan were in-

vestigated [5].

Geroprotector must reverse processes associated with

age-related diseases. Clinical trials or use of geroprotector

in modern medical practice is impossible without some

symptoms associated with the diseases developed in an

individual. Hence, geroprotector should provide certain

help with the symptoms of age-related diseases in order

to have chance to be accepted in medical practice. Nev-

ertheless, geroprotectors could be potentially assigned

to a new class of medicinal drugs, prophylactic agents,

because they not only treat the symptoms of certain dis-

eases, but also create background for resistance to the de-

velopment of certain diseases or slowing down their onset

and progression. Vladimir Dilman, expert in gerontol-

ogy, named aging a universal disease[6]. According to

Mikhail Blagosklonnyi, age-related diseases (type 2 dia-

betes, Alzheimer’s disease, cardiovascular diseases) are

symptoms of aging, same as smoke is a sign of fire[7].

Hence, effectiveness of a geroprotector should be as-

sessed on its ability to delay onset of several age-related

diseases in humans (prevent multimorbidity) and extent

healthy lifespan (age before the first chronic disease

develops).

Geroprotector should provide positive effect on bio-

markers of human aging. Biomarkers of aging are molec-

ular, cellular, physiological, and psychological parame-

ters of an organism, which are known to change reliably,

qualitatively, and quantitatively in aging [8]. The gero-

protector candidate should change these parameters to

the state typical for a younger age. The criteria of gero-

protectors associated with aging biomarkers are of spe-

cial importance for translation of the results into medi-

cal practice. Investigation of lifespan of a human treated

with geroprotector candidate are very lengthy and cost-

ly. Hence, analysis of lifespan could be performed with

animals, and effects on the human aging could be elu-

cidated based on the wide spectrum of changes of bio-

markers resulting from the geroprotective therapy. Cur-

rently there have been many attempts to use estimates

of biological age as a complex biomarker of human ag-

ing in the randomized placebo-controlled clinical trials.

Inparticular, change in the thickness of the intima-me-

dia complex of carotid artery and rigidity of the arterial

wall after treatment with the complex terpene prepara-

tion was demonstrated [9].

Geroprotector should not exhibit any pronounced

side effects and should improve quality of life. Consider-

ing that some geroprotectors could exhibit prophylactic

effect only at a relatively high concentration, toxic and

most effective (from the point of view of slowing down

aging) concentrations should differ as much as possible.

Some compounds that extent lifespan of animals at cer-

tain doses, exhibit side effects in humans. Achieving a

geroprotective effect implies long-term (many years) ad-

ministration of the preparation. Use of such preparation

would require to compromise between the expected and

side effects. Hence, it is preferably that the number and

manifestation of side effects for the geroprotector candi-

date would be minimal. Efficiency of slowing down ag-

ing under the influence of geroprotectors, mostly likely,

would be noticeable only after many years of taking the

preparation on the regular basis. Hence, it is important

that they would be capable of improving quality of life

form the very beginning of their administration– facil-

itate elimination of digestive problems, affect favorably

sleeping patterns, prevent development of depression or

memory loss.

We applied the criteria for geroprotectors to a wide

range of potential geroprotectors. The criteria are met

for some natural terpenoids [10] and compounds exhib-

iting protective effect on the genome [11].

Professor V. N. Anisimov classified the life-extend-

ing compounds into three groups [12]. The first group in-

cludes geroprotectors that are equally useful for all mem-

bers of population, because they could delay the onset

of aging. The second group includes geroprotectors that

reduce mortality of individuals at advanced age. Theyal-

low to increase maximum life expectancy by slowing

down the process of population aging. The third group

are geroprotectors that increase the chances of survival of

humans at middle age without increasing maximum life

expectancy in the population. This means that they speed

up the process of aging, but at the same time increase the

probability for the individual to live to old age.

Aging could be defined as gradual reduction of the

capability of the organism’s systems to maintain stability

of inner milieu, which leads to onset of age-related dis-

eases and death. That is why the main strategy in fight-

ing aging and preventing wearing out of the body could

be maintenance of homeostatic capabilities at all levels

of organization of a live system.

Classification of geroprotectors according to their

ability to maintain homeostasis of an organism [13].

Correction of the consequences of homeostasis disruption.

Disruption of homeostasis with age is manifested by de-

viation from the healthy level of such vital parameters as

blood acid-base balance, arterial blood pressure, level of

glucose and cholesterol in blood. Hence, preparations

preventing development of such age-related states could

be considered as geroprotectors. Geroprotectors that

correct consequences of homeostasis disruption could

include antidiabetic, antiarrhythmic, hypolipidemic, vas-

cular, and antihypertension preparations. Indeed, such

preparations as antidiabetic biguanides (metformin) and

sodium glucose cotransporter 2 inhibitors (SGLT2l) are

capable of decreasing cardiovascular mortality, beyond

the limits of secondary prevention[14, 15]. Bisphospho-

nates (inhibitors of bone resorption) also decrease overall

mortality of the patients [16]. Stable reduction of mortal-

ity was demonstrated for the 65 years old and older pa-

tients taking statins [17].

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Table 1. Mechanisms of action of potential geroprotectors [23]

Mechanism Group of geroprotectors Examples

Prevention

of free radical oxidation

free radical scavengers or antioxidants;

transition metal chelators;

fatty acids resistant to lipid peroxidation

vitamins C, A, E,

deuterated polyunsaturated

fatty acids

Maintenance

of mitochondrial functions

mitohormetins and inhibitors

of mitochondrial electron transport chain;

inducers of mitophagy;

activators of PPARy/PGC-1α and mitoproliferation;

NAD

precursors

urolithin A,

NMN, NR, NA

Maintenance of proteostasis agent preventing glycation, and inhibitors

of crosslinking of advanced glycation end

products (AGEs);

antagonists of AGEs receptors, RAGE;

anti-amyloid compounds;

stimulators of extracellular matrix metabolism;

inducers of autophagy;

proteasome activators;

transient translation inhibitors

spermidine

Senolytics/senostatics compounds facilitating selective elimination

of senescent cells or slowing down their emergence

quercetin + dasatinib

Hormetins compounds inducing moderate damage

and stimulating activation of defence mechanisms

of stress resistance

sulforaphane, curcumin

Suppressors

of genome instability

antimutagen compounds;

telomere stabilizers;

inhibitors of retrotransposition

inhibitors of reverse

transcriptase

Epigenetic regulators inhibitors of HDACs, HATs;

activators of SIRTs

butyrate,

beta-hydroxybutyrate,

resveratrol

Inhibitors

of ageing-associated pathways

inhibitors of mTORC1; inhibitors of PI3K;

inhibitors of Ras; inhibitors of Myc;

inhibitors of AT1; activators of AMPK;

Klotho activators

rapamycin, torin2,

wortmannin, LY294002

Anti-inflammatory preparations

inhibitors of NF-κB; activators of NRF2

ibuprofen, aspirin

Gut microbiota optimizers prebiotics, metabiotics, and enterosorbents dietary fibers, lignans

Anti-fibrotic agents inhibitors of fibrosis-associated signaling pathways inhibitors

of TGF-β→ALK5→

→p-Smad2,3 pathway

Neurotrophic factors plat role in development and maintenance

of structures in central and peripheral nervous systems

BDNF mimetics

Factors preventing disruption

of barrier function

inhibitors of matric metalloproteinases,

activators of synthesis of tight junction proteins

MMP9 inhibitors

Immunomodulators factors facilitating thymus regeneration

and preservation of the pool of naïve T-cells

regulators

of JAK→STAT pathway

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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023

Table 2. Clinical trials of potential geroprotectors

Group Indication References

Inhibitor of mTOR,

RTB101

immunity to viral infection in elderly [32]

AMPK modulator,

metformin

cardiovascular diseases [33]

Activator of Nrf2-pathway,

sulforaphane

alleviation of symptoms of mild and moderated depression in the patients

with cardiological surgeries in anamnesis

[34]

Reduction of NAD

supplementing with NAD

precursors (nicotinamide, nicotinamide riboside,

nicotinamide mononucleotide) positively affect biomarkers of lipid profile

in the patients with cardiovascular diseases and dyslipidemia

[35]

Senolytics

quercetin + dasatinib decrease the level of inflammation in adipose tissues

and improve systemic metabolic function in elderly

[36]

Enhancement of capabilities of homeostatic systems

of an organism. At the cellular level the key homeostatic

role is played by the stress response proteins. Nutrient

deficiencies, hypoxia, DNA damage, disruptions of ho-

meostasis are perceived by the cell as stress. Activation

of the stress-resistance systems could not only alleviate

damages, but also could transform the system to the

higher level of defence against the new spontaneous er-

rors and damages [18]. Induction of the stress-resistance

mechanisms could be realized by the factors causing

moderate stress that do not induce damage, but capa-

ble of activating defence. This phenomenon was termed

“hormesis” [19], and compounds causing it were named

hormetins [20].

Neutralization of the agents causing disruptions in

homeostasis in external and internal environment. This

is a wide group of compounds including, for example,

chelators of transition metals Cu and Fe participating in

the Fenton, Haber–Weiss, and Maillard reactions; scav-

engers of reactive oxygen species; compounds cleaving

crosslinks; preparations preventing protein aggregation

(anti-amyloid compounds).

Suppression of excessive homeostatic reaction causing

further loss of homeostasis. Hyperactivation of some ho-

meostatic reaction in response to stress could cause even

more severe damage than the initial damage. Accord-

ing to the hypothesis of geroconversion suggested by

M. B. Blagosklonny, after the cell cycle arrest the aging

cells continue their growth. Geroconversion results in

hypersecretion, hypertrophy, and proinflammatory cell

phenotype, which depends on activity of the mTOR ki-

nase [21]. Inflammaging postulated by Franceschi [22]

could be considered as such excessive homeostatic reac-

tion. Preparations targeting specific targets hyperactivat-

ed in aging (mTORC1, NF-κB, PARP1, iNOX, COX2,

p38, S6K, TGF-β, AT1, IGFR, HIF-1) could also be

also considered as inhibitors of hyperactivation.

At present the number of investigated targets of po-

tential geroprotectors is very limited, and their efficien-

cy in prolonging life leaves much to be desired. One of

the potential approaches to expand the list of effective

targets is to include in consideration a wider spectrum

of molecular, cellular, and systemic processes associated

with age-related diseases (Table 1). However, it must be

mentioned that each individual compound could affect

several pathways, and each geroprotector could belong

to several subclasses.

To increase the number of potential effective targets

of geroprotectors it has been suggested to use comput-

erized search algorithm based on comparison of tran-

scriptomic signature of old and young cells [24]. Real-

ization of such approach allowed establishing potential

geroprotective properties in some FDA approved drugs

such as pioglitazone (PPARγ agonist)[25]. New targets

for potential drugs with anti-aging properties and as-

sociated with treatment of 14 age-related diseases were

identified with the help of the specialized computer pro-

gram, PandaOmics, that uses a set of artificial intelli-

gence algorithms. In particular, several gene targets were

found that play an important role in the processes of in-

flammation and in rigidity of extracellular matrix in the

organism tissues. These genes include CASP3, VEGFA,

and MMP9[26].

Another way to increase efficiency of geroprotection

is combination of several targets associated with aging in

one intervention. Combining rapamycin with wortman-

nin increased drosophila lifespan by 23.4% [27]. Prepa-

rations affecting TGF-β and IGF-1 pathways synergis-

tically increased the lifespan of Caenorhabditis elegans

up to 2-fold [28]. Simultaneous inhibition of TGF-β

and treatment with oxytocin enhance neurogenesis,

decrease neuroinflammation, improve cognitive func-

tions, rejuvenate liver and muscles, and decrease the

number of aging cells expressing p16 in old mice [29].

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Year-long treatment of the patients with recombinant

human growth hormone together with dehydroepi-

androsterone(DHEA) and metformin changes epigen-

etic age by approximately 1.5 years [30].

Problems associated with application of geropro-

tectors should be also considered [31]. Majority of gero-

protectors investigated in the model organisms increase

lifespan only marginally or only in the animals of one sex.

Aging is not recognized as a disease or pathological state,

which explains low number of clinical trials of pharma-

ceuticals, practically limiting them to investigation of

natural compounds in composition of biologically ac-

tive supplements. Absence of the generally accepted set

of biomarkers of human aging also complicates clinical

studies of potential geroprotectors.

The available clinical data are quite limited and

provide information only on usefulness of potential

geroprotectors with regards to surrogate health markers

and mainly for the patients with age-related diseases,

but not for the healthy individuals (Table2).

Considering that the main goal of application of

geroprotectors is extension of human healthspan, pro-

spectively treatment should start before the development

of the first chronic age-related disease. At present we

can only talk about gerosuppressors, because they help

to prevent or to slow down some manifestations of ag-

ing; so far there is no clinically proven strategies to re-

verse aging.

CONCLUSIONS

Despite the existence of numerous known mecha-

nisms for prophylactics of aging, many geroprotectors

have been poorly investigated even at the preclinical

stage. It is difficult to draw any far-reaching conclusions,

because there are no sufficient data to examine if poten-

tial geroprotectors meet the required criteria. Side effects

could be more significant than the potential benefits in

the long term. Some potential geroprotectors showed

very promising results in the studies with animal mod-

els, but their efficiency must be confirmed in the pla-

cebo-controlled, blind, multi-center clinical trials using

biomarkers of human aging and mortality data.

The goal of using geroprotector is extension of

healthy life, and treatment should start before mani-

festations of chronic diseases in order to delay onset of

the first are-related chronic disease. However, it is very

difficult to obtain approval for such clinical trial with-

out declaration of any symptoms/indications, especially

due to the serious side effects of some preparations with

pre-clinically proven geroprotective activity, such as

EDTA and rapamycin. It seems more promising, in our

opinion, to examine biologically active supplements in

clinical setting using biomarkers of aging as check points

as well as methods for evaluation of biological age.

At present we can talk not about geroprotectors,

but about gerosuppressors, because we can slow down

but not prevent development of some manifestations of

aging. However, new methods fighting aging could ap-

pear in future, and we hope for development of the new

branch of medicine, medicine of healthy longevity, in

our country, similar to the recently created clinical cen-

ters in Singapore, Hong Kong, and USA.

Acknowledgments. The author is grateful to his col-

leagues and collaborators participating in our studies of

geroprotectors cited in this review.

Funding. This work was financially supported by

the Program “Prioritet 2030” of the Nizny Novgorod

State University “Healthy Generation”.

Ethics declarations. The author declares no conflict

of interests in financial or any other sphere. This article

does not contain any studies with human participants or

animals performed by the author.

REFERENCES

1. Fomenko, A. M., Proshkina, E. N., Fedintsev, A. Yu.,

Tsvetkov, V. O., Shaposhnikiv, M. V., and Moskalev,

A. A. (2016) Potential Geroprotectors, Evropeisky Dom,

St.-Petersburg.

2. Bischof, E., Scheibye-Knudsen, M., Siow, R., and Moska-

lev, A. (2021) Longevity medicine: upskilling the physi-

cians of tomorrow, Lancet Healthy Longev., 2, e187-e188,

doi:10.1016/S2666-7568(21)00024-6.

3. Moskalev, A., Chernyagina, E., Tsvetkov, V., Fedint-

sev,A., Shaposhnikov, M., Krut’ko, V., Zhavoronkov,A.,

and Kennedy, B.K. (2016) Developing criteria for eval-

uation of geroprotectors as a key stage toward transla-

tion to the clinic, Aging Cell, 15, 407-415, doi: 10.1111 /

acel.12463.

4. Moskalev, A., Chernyagina, E., de Magalhaes, J. P., Ba-

rardo, D., Thoppil, H., Shaposhnikov, M., Budovsky,A.,

Fraifeld, V. E., Garazha, A., Tsvetkov, V., Bronovitsky,E.,

Bogomolov, V., Scerbacov, A., Kuryan, O., Gurinovich,R.,

Jellen, L. C., Kennedy, B., Mamoshina,P., Dobrovolska-

ya, E., Aliper, A., etal. (2015) Geroprotectors.org: a new,

structured and curated database of current therapeutic in-

terventions in aging and age-related disease, Aging (Albany

NY), 7, 616-628, doi:10.18632/aging.100799.

5. Barardo, D., Thornton, D., Thoppil, H., Walsh, M.,

Sharifi, S., Ferreira, S., Anzic, A., Fernandes, M., Mon-

teiro, P., Grum, T., Cordeiro, R., De-Souza, E. A.,

Budovsky, A., Araujo, N., Gruber, J., Petrascheck, M.,

Fraifeld, V. E., Zhavoronkov, A., Moskalev, A., and

deMagalhaes, J. P. (2017) TheDrugAge database of ag-

ing-related drugs, Aging Cell, 16, 594-597, doi: 10.1111/

acel.12585.

6. Dilman, V. M. (1986) The Grand Biological Clock. Introduc-

tion to Integral Medicine [in Russian], Znaniye, Moscow.

POTENTIAL GEROPROTECTORS 1737

BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023

7. Blagosklonny, M. V. (2009) TOR-driven aging: speeding

car without brakes, Cell Cycle, 8, 4055-4059, doi:10.4161/

cc.8.24.10310.

8. Moskalev, A. (2020) The challenges of estimating biologi-

cal age, Elife, 9, e54969, doi:10.7554/eLife.54969.

9. Maganova, F., Voevoda, M., Popov, V., and Moska-

lev, A. (2023) A prospective randomized comparative

placebo-controlled double-blind study in two groups

to assess the effect of the use of biologically active addi-

tives with Siberian fir terpenes for the biological age of a

person, Front. Pharmacol., 14, 1150504, doi: 10.3389/

fphar.2023.1150504.

10. Proshkina, E., Plyusnin, S., Babak, T., Lashmano-

va,E., Maganova, F., Koval, L., Platonova, E., Shaposh-

nikov,M., and Moskalev, A. (2020) Terpenoids as potential

geroprotectors, Antioxidants (Basel), 9, 529, doi:10.3390/

antiox9060529.

11. Proshkina, E., Shaposhnikov, M., and Moskalev, A.

(2020) Genome-protecting compounds as potential

geroprotectors, Int. J. Mol. Sci., 21, 4484, doi:10.3390/

ijms21124484.

12. Anisimov, V. N. (2001) Life span extension and can-

cer risk: myths and reality, Exp. Gerontol., 36, 1101-1136,

doi:10.1016/s0531-5565(01)00114-0.

13. Moskalev, A., Chernyagina, E., Kudryavtseva, A., and

Shaposhnikov, M. (2017) Geroprotectors: aunified con-

cept and screening approaches, Aging Dis., 8, 354-363,

doi:10.14336/AD.2016.1022.

14. Araldi, E., Jutzeler, C. R., and Ristow, M. (2023) Ef-

fects of antidiabetic drugs on mortality risks in individu-

als with type2 diabetes: Aprospective cohort study of UK

Biobank participants, medRxiv, doi: 10.1101/2023.05.19.

23290214.

15. Roussel, R., Travert, F., Pasquet, B., Wilson, P. W., Smith,

S. C., Jr., Goto, S., Ravaud, P., Marre, M., Porath, A.,

Bhatt, D. L., Steg, P. G., and Reduction of Atherothrom-

bosis for Continued Health Registry Investigators (2010)

Metformin use and mortality among patients with diabetes

and atherothrombosis, Arch. Intern. Med., 170, 1892-1899,

doi:10.1001/archinternmed.2010.409.

16. Bergman, J., Nordstrom, A., Hommel, A., Kivipelto, M.,

and Nordstrom, P. (2019) Bisphosphonates and mortality:

confounding in observational studies? Osteoporos. Int., 30,

1973-1982, doi:10.1007/s00198-019-05097-1.

17. Gitsels, L. A., Bakbergenuly, I., Steel, N., and Kulinska-

ya, E. (2021) Do statins reduce mortality in older peo-

ple? Findings from a longitudinal study using primary

care records, Fam. Med. Community Health, 9, e000780,

doi:10.1136/fmch-2020-000780.

18. Moskalev, A. A., Aliper, A. M., Smit-McBride, Z.,

Buzdin, A., and Zhavoronkov, A. (2014) Genetics and epi-

genetics of aging and longevity, Cell Cycle, 13, 1063-1077,

doi:10.4161/cc.28433.

19. Calabrese, E. J. (2013) Hormesis: toxicological foun-

dations and role in aging research, Exp. Gerontol., 48,

99-102, doi:10.1016/j.exger.2012.02.004.

20. Rattan, S. I. (2012) Rationale and methods of discovering

hormetins as drugs for healthy ageing, Expert Opin. Drug

Discov., 7, 439-448, doi:10.1517/17460441.2012.677

430.

21. Blagosklonny, M. V. (2014) Geroconversion: irreversible

step to cellular senescence, Cell Cycle, 13, 3628-3635,

doi:10.4161/15384101.2014.985507.

22. Franceschi, C. (2007) Inflammaging as a major character-

istic of old people: can it be prevented or cured? Nutr. Rev.,

65, S173-S176, doi:10.1111/j.1753-4887.2007.tb00358.x.

23. Moskalev, A., Guvatova, Z., Lopes, I. A., Beckett, C.W.,

Kennedy, B. K., De Magalhaes, J. P., and Makarov,

A.A. (2022) Targeting aging mechanisms: pharmacolog-

ical perspectives, Trends Endocrinol. Metab., 33, 266-280,

doi:10.1016/j.tem.2022.01.007.

24. Zhavoronkov, A., Buzdin, A. A., Garazha, A. V., Bor-

isov, N.M., and Moskalev, A.A. (2014) Signaling path-

way cloud regulation for in silico screening and ranking

of the potential geroprotective drugs, Front. Genet., 5, 49,

doi:10.3389/fgene.2014.00049.

25. Yang, J., Peng, S., Zhang, B., Houten, S., Schadt, E.,

Zhu, J., Suh, Y., and Tu, Z. (2020) Human geroprotec-

tor discovery by targeting the converging subnetworks of

aging and age-related diseases, Geroscience, 42, 353-372,

doi:10.1007/s11357-019-00106-x.

26. Pun, F. W., Leung, G. H. D., Leung, H. W., Liu, B.H.M.,

Long, X., Ozerov, I. V., Wang, J., Ren, F., Aliper, A.,

Izumchenko, E., Moskalev, A., de Magalhaes, J.P., and

Zhavoronkov, A. (2022) Hallmarks of aging-based du-

al-purpose disease and age-associated targets predicted

using PandaOmics AI-powered discovery engine, Aging

(Albany NY), 14, 2475-2506, doi:10.18632/aging.203960.

27. Danilov, A., Shaposhnikov, M., Plyusnina, E., Kogan, V.,

Fedichev, P., and Moskalev, A. (2013) Selective anticancer

agents suppress aging in Drosophila, Oncotarget, 4, 1507-

1526, doi:10.18632/oncotarget.1272.

28. Admasu, T. D., Chaithanya Batchu, K., Barardo, D., Ng,

L. F., Lam, V. Y. M., Xiao, L., Cazenave- Gassiot, A.,

Wenk, M.R., Tolwinski, N.S., and Gruber, J. (2018) Drug

synergy slows aging and improves healthspan through

IGF and SREBP lipid signaling, Dev. Cell, 47, 67-79.e65,

doi:10.1016/j.devcel.2018.09.001.

29. Mehdipour, M., Etienne, J., Chen, C. C., Gathwala, R.,

Rehman, M., Kato, C., Liu, C., Liu, Y., Zuo, Y., Con-

boy, M. J., and Conboy, I. M. (2019) Rejuvenation of

brain, liver and muscle by simultaneous pharmacological

modulation of two signaling determinants, that change

in opposite directions with age, Aging (Albany NY), 11,

5628-5645, doi:10.18632/aging.102148.

30. Fahy, G. M., Brooke, R. T., Watson, J. P., Good, Z.,

Vasanawala, S. S., Maecker, H., Leipold, M.D., Lin, D.

T. S., Kobor, M.S., and Horvath, S. (2019) Reversal of

epigenetic aging and immunosenescent trends in humans,

Aging Cell, 18, e13028, doi:10.1111/acel.13028.

31. Moskalev, A. (2020) Is anti-ageing drug discovery be-

coming a reality, Expert Opin. Drug Discov., 15, 135-138,

wdoi:10.1080/17460441.2020.1702965.

MOSKALEV1738

BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023

32. Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell,

K., Klickstein, L., Marshall, W., and Shergill, S. (2021)

Targeting the biology of ageing with mTOR inhibitors to

improve immune function in older adults: phase 2b and

phase 3 randomised trials, Lancet Healthy Longev., 2,

e250-e262, doi:10.1016/S2666-7568(21)00062-3.

33. Dihoum, A., Rena, G., Pearson, E. R., Lang, C.C., and

Mordi, I. R. (2023) Metformin: evidence from preclin-

ical and clinical studies for potential novel applications

in cardiovascular disease, Expert Opin. Invest. Drugs, 32,

291-299, doi:10.1080/13543784.2023.2196010.

34. Ghazizadeh-Hashemi, F., Bagheri, S., Ashraf-

Ganjouei, A., Moradi, K., Shahmansouri, N., Mehr-

pooya, M., Noorbala, A.A., and Akhondzadeh, S. (2021)

Efficacy and safety of sulforaphane for treatment of mild

to moderate depression in patients with history of cardiac

interventions: Arandomized, double-blind, placebo-con-

trolled clinical trial, Psychiatry Clin. Neurosci., 75, 250-

255, doi:10.1111/pcn.13276.

35. Zhong, O., Wang, J., Tan, Y., Lei, X., and Tang, Z. (2022)

Effects of NAD

precursor supplementation on glucose

and lipid metabolism in humans: a meta-analysis, Nutr.

Metab. (Lond), 19, 20, doi:10.1186/s12986-022-00653-9.

36. Islam, M. T., Tuday, E., Allen, S., Kim, J., Trott, D.W.,

Holland, W.L., Donato, A.J., and Lesniewski, L.A. (2023)

Senolytic drugs, dasatinib and quercetin, attenuate adipose

tissue inflammation, and ameliorate metabolic function

in old age, Aging Cell, 22, e13767, doi:10.1111/acel.13767.