Article

ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 2, pp. 367-370 © Pleiades Publishing, Ltd., 2024.

367

MINI-REVIEW

Two Types of Survival Curves

of Different Lines of Progeric Mice

Svyatoslav S. Sokolov

and Fedor F. Severin

1,a

Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

e-mail: severin@belozersky.msu.ru

Received August 26, 2023

Revised December 2, 2023

Accepted December 29, 2023

Abstract— For most of their lifespan, the probability of death for many animal species increases with age. Gompertz

law states that this increase is exponential. In this work, we have compared previously published data on the sur-

vival kinetics of different lines of progeric mice. Visual analysis showed that in six lines of these rapidly aging mu-

tants, the probability of death did not strictly depend on age. In contrast, ten lines of progeric mice have survival

curves similar to those of the control animals, that is, in agreement with Gompertz law, similar to the shape of an

exponential curve upside down. Interestingly, these ten mutations cause completely different cell malfunctions.

We speculate that what these mutations have in common is a reduction in the lifespan of cells and/or an acceler-

ation of the transition to the state of cell senescence. Thus, our analysis, similar to the conclusions of many previ-

ously published works, indicates that the aging of an organism is a consequence of the aging of individual cells.

DOI: 10.1134/S0006297924020147

Keywords: progeria, survival curves, Gompertz law, aging

* To whom correspondence should be addressed.

Since the mid-nineties, Vladimir Petrovich Skulachev has worked a lot on various aspects of the aging

process. Certainly, there was some synergy between his work on the theory of phenoptosis and his medically

important project on Skulachev ions. There were many articles on the topic of aging, a book, there were sever-

al conferences. There were seminars on Thursdays. Once he is gone, interest in the basic aspects of aging has

somehow faded in our institute. I take this opportunity to address the readers of the journal Biochemistry

(Moscow), the participants of those seminars: should we resume Thursday’s seminars on gerontology? Are all

our common intellectual efforts on the topic of aging already in the past?

Of course, he and I discussed the issues of aging not only at seminars, but also at home, well, or on a walk

with the dog. I miss these conversations. I think he would be interested in one curious fact that came to light

in the process of reading literature on rapidly aging mice.

Fedor

INTRODUCTION

Mice with mutations that cause accelerated aging

are widely used in laboratory practice. In particular,

this is done so that experiments on the lifespan of mice

do not take too much time. It is important to distin-

guish progeric mutations from mutations that simply

shorten the lifespan of an animal. Progeric animals

are those, whose life expectancy is significantly lower

than the control ones, and at the same time, with age,

they exhibit typical signs of aging, such as kyphosis, at-

rophy of fat and muscle tissue, cardiomyopathy, and a

number of others (see review [1]). Oddly enough, the

set of these traits does not include the shape of the

mouse survival curve. It is well known that the prob-

ability of death, for the most of the lifespan, increas-

es with age according to an exponential relationship.

This is Gompertz law, which governs the survival ki-

netics of mice, humans, and many other living beings

(see review [2]). In this work, we tried to determine

SOKOLOV, SEVERIN368

BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

Two types of survival curves of progeric mice. Panels(a) and(b) show the curves similar to those of control animals. The curves

in panels(c) and(d) are visually different from those presented in panels(a) and(b). The graphs are based on data from

theworks cited in the text.

which of the progeric mouse strains have (or are simi-

lar to) the inverted exponential shape of their survival

curves, according to Gompertz law.

SURVIVAL CURVES OF PROGERIC MICE

Visual analysis of the shapes of the curves showed

that they are of two types. One type of curve is similar to

that of control mice, that is, apparently consistent with

Gompertz’s law. The second type of curves differs sig-

nificantly from the first. It can be assumed that in these

progeric mice the probability of death does not strictly

depend on age. Figure(a and b) shows the examples

of survival curves of the first type; figure(c andd) –

the ones of the second type. Graphs represent: a) the

survival curve of the LmnaG608G mutant; b) Ercc1

–/–

mutant; c) BubR1H/H mutant; d) AIMP3Tg mutant. The

graphs were made based on the data presented in[3-6],

respectively.

Table shows the majority of progeric mouse

strains used in laboratory practice (see table 5.2 of

the review [1]). According to the results of the visual

analysis, these lines are divided into two groups: those

whose survival curves are similar to the curves in fig-

ure (a and b) and those that are similar to those of fig-

ure (b and d). As can be seen from table, the survival

curves of ten mutant lines are similar to those of con-

trol mice, as in figure (a and b, left column).

It is noteworthy that the mutations presented in

the left column of table are of a completely differ-

ent nature. They affect lamin A, nuclear DNA repair,

mitochondrial DNA replication, protection from ox-

idative stress, histone deacetylation, tumor growth

suppression. However, these very different interven-

tions in cell physiology apparently have a very simi-

lar result at the organismal level: acceleration of ag-

ing kinetics in agreement with Gompertz law. How

can this be explained? It is possible that all of these

mutations, each in its own unique way, either reduce

the lifespan of cells or accelerate the transition to a

state of senescence. Indeed, it is well known that the

tissue composition of organs changes with aging. For

example, in skeletal muscles, myofibrils undergo at-

rophy and are then replaced by cells of adipose and

connective tissue. In addition, in various tissues, the

proportion of cells in the senescence state increases

with age.

SURVIVAL CURVES OF PROGERIC MICE 369

BIOCHEMISTRY (Moscow) Vol. 89 No. 2 2024

Mutations that cause accelerated aging in mice and the functions of the proteins encoded by the mutated genes

Progeric mice with the survival curves

of similar shapes to the control animals

Progeric mice without visual dependency

of death probability on the age

Lmna

G608G

, lamin A,

structural protein of nuclear envelope

ku86

–/–

, recombination,

double strand DNA break reparation

Xpd

–/–

, DNA repair top3B

–/–

, topoisomerase

Ercc1

–/–

, DNA repair BubR1

h/h

, mitotic checkpoint

PolgA

(mut)

, mitochondrial DNA polymerase Terc1

–/–

Atm

–/–

, telomere maintenance

Sod1

–/–

, superoxide dismutase Sirt1

–/–

, deacetylation of histones

MsrA

–/–

, methionine sulfoxidereductase AIMP3Tg, tumor suppressor

p62

–/–

, adaptor protein, autophagy,

and oxidative stress

–

Mtr

–/–

, telomerase –

Sirt6

–/–

, deacetylation of histones –

p53

+/m

, tumor suppressor –

In other words, this observation provides further

evidence that the primary cause of aging is the aging

of individual cells, and not, for example, age-related

changes in cell–cell interactions. The fact that proger-

ic mutations shorten the lifespan of cultured cells is

shown for at least two mutations presented in the left

column of table. There is evidence that the aging of pri-

mary fibroblasts collected from patients with progeria

caused by a mutation in laminA occurs faster than in

the control cells [7]. The same is observed in blood cell

precursors (hematopoetic progenitors) from proger-

ic mice with a knockout Ercc1 (DNA repair) gene [8].

These two studies examined so-called replicative aging.

It should be noted that there are two types of ex-

perimental models of the aging of cultured cells: repli-

cative and chronological. Most of the work in this area

is devoted to replicative aging. Thus, it was shown that

the number of divisions of primary fibroblasts is limit-

ed by the Hayflick limit. Chronological aging is due to

the fact that after reaching the monolayer state, cell di-

vision stops, and after some time the cells begin to die.

Both models have their limitations, but are successfully

used to search for geroprotectors [9].

Finally, one can ask: can geroprotectors or genet-

ic interventions change the type of survival curve of

progeric mice? We were unable to find examples of

the transformation of a curve of the first type (visually

obeying the Gompertz law) into a curve of the second

type. For example, the mitochondrially targeted anti-

oxidant SkQ1 significantly increases the lifespan of

PolgA(mut) mice, but the shape of the survival curve

does not change ([10], Fig.9). Curves of the second type

can change. Thus, the deletion of p21 gene, whose ex-

pression is activated by DNA damage, prolongs the life

of mice with the deletion of telomerase Terc1. Inthis

case, the shape of the survival curve becomes visually

similar to an inverted exponential ([11], Fig.1).

Contributions. Both authors contributed equally

to this work.

Funding. This work was supported by the Russian

Science Foundation (grant no.22-24-00533).

Ethics declarations. This work does not contain

any studies involving human and animal subjects.

The authors of this work declare that they have no

conflicts of interest.

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