ÃÅÐÎÍÒÎËÎÃÈß ÒÅÑÒÈÐÎÂÀÍÈÅ ÃÅÐÎÏÐÎÒÅÊÒÎÐΠ ÝÊÑÏÅÐÈÌÅÍÒÀÕ ÍÀ ÊËÅÒÎ×ÍÛÕ ÊÓËÜÒÓÐÀÕ: ÂÛÁÎÐ ÎÏÒÈÌÀËÜÍÎÉ ÌÎÄÅËÜÍÎÉ ÑÈÑÒÅÌÛ

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ÂÅÑÒÍ. ÌÎÑÊ. ÓÍ-ÒÀ. ÑÅÐ. 16. ÁÈÎËÎÃÈß. 2014. ¹ 1
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ÃÅÐÎÍÒÎËÎÃÈß
ÓÄÊ 576.35:57.017.6
ÒÅÑÒÈÐÎÂÀÍÈÅ ÃÅÐÎÏÐÎÒÅÊÒÎÐÎÂ
 ÝÊÑÏÅÐÈÌÅÍÒÀÕ ÍÀ ÊËÅÒÎ×ÍÛÕ ÊÓËÜÒÓÐÀÕ:
ÂÛÁÎÐ ÎÏÒÈÌÀËÜÍÎÉ ÌÎÄÅËÜÍÎÉ ÑÈÑÒÅÌÛ
À.Í. Õîõëîâ, À.À. Êëåáàíîâ, À.Ô. Êàðìóøàêîâ, Ã.À. Øèëîâñêèé,
Ì.Ì. Íàñîíîâ, Ã.Â. Ìîðãóíîâà
(ñåêòîð ýâîëþöèîííîé öèòîãåðîíòîëîãèè; e-mail: [email protected])
Alive or dead are those cells
We study in our flasks and wells?
Àâòîðû ñ÷èòàþò, ÷òî öèòîãåðîíòîëîãè÷åñêèå ìîäåëè òèïà ìîäåëè Õåéôëèêà õîòÿ è î÷åíü
ïîëåçíû äëÿ ýêñïåðèìåíòàëüíîé ãåðîíòîëîãèè, íî îñíîâàíû ëèøü íà îïðåäåëåííûõ êîððåëÿöèÿõ è íå ñâÿçàíû íàïðÿìóþ ñ ñóòüþ ïðîöåññà ñòàðåíèÿ. Ñ ïîìîùüþ “ôåíîìåíà Õåéôëèêà” íåâîçìîæíî êîððåêòíî îáúÿñíèòü, ïî÷åìó ìû ñòàðååì. Íàïðîòèâ, ìîäåëü “ñòàöèîíàðíîãî
ñòàðåíèÿ”, ñóäÿ ïî âñåìó, ÿâëÿåòñÿ “ñóùíîñòíîé” ìîäåëüþ, èáî îñíîâàíà íà ãèïîòåçå, ñîãëàñíî
êîòîðîé îñíîâíîé ïðè÷èíîé êàê ïðîèñõîäÿùèõ â êëåòêàõ ñòàöèîíàðíûõ êóëüòóð “âîçðàñòíûõ”
èçìåíåíèé, òàê è ñîîòâåòñòâóþùèõ èçìåíåíèé êëåòîê ñòàðåþùèõ ìíîãîêëåòî÷íûõ îðãàíèçìîâ ÿâëÿåòñÿ îãðàíè÷åíèå êëåòî÷íîé ïðîëèôåðàöèè. Ìîäåëü ïðèìåíèìà äëÿ ýêñïåðèìåíòîâ
íà ñàìûõ ðàçíûõ êóëüòèâèðóåìûõ êëåòêàõ, âêëþ÷àÿ íîðìàëüíûå è òðàíñôîðìèðîâàííûå êëåòêè ÷åëîâåêà è æèâîòíûõ, ðàñòèòåëüíûå êëåòêè, áàêòåðèè, äðîææè, ìèêîïëàçìû è äð. Ðåçóëüòàòû ñîîòâåòñòâóþùèõ ýêñïåðèìåíòîâ ñâèäåòåëüñòâóþò î òîì, ÷òî âûìèðàíèå êëåòîê â ìîäåëè
“ñòàöèîíàðíîãî ñòàðåíèÿ” ïðîèñõîäèò â ñîîòâåòñòâèè ñ çàêîíîì Ãîìïåðòöà, îïèñûâàþùèì
ýêñïîíåíöèàëüíîå óâåëè÷åíèå ñî âðåìåíåì âåðîÿòíîñòè ãèáåëè. Ïðåäïîëàãàåòñÿ, ÷òî ìîäåëü
“ñòàöèîíàðíîãî ñòàðåíèÿ” ìîæåò îáåñïå÷èâàòü äîñòàòî÷íî ýôôåêòèâíîå òåñòèðîâàíèå ãåðîïðîòåêòîðîâ (ôàêòîðîâ, çàìåäëÿþùèõ ñòàðåíèå) è ãåðîïðîìîòîðîâ (ôàêòîðîâ, åãî óñêîðÿþùèõ)
â öèòîãåðîíòîëîãè÷åñêèõ ýêñïåðèìåíòàõ.  òî æå âðåìÿ àâòîðû ïîä÷åðêèâàþò, ÷òî äàæå ðåçóëüòàòû òàêèõ ýêñïåðèìåíòîâ â íåêîòîðûõ ñëó÷àÿõ íå ñîâïàäàþò ñ äàííûìè, ïîëó÷åííûìè
in vivo, òàê ÷òî íå ìîãóò ñ÷èòàòüñÿ îêîí÷àòåëüíûìè è òðåáóþò îáÿçàòåëüíîé ïåðåïðîâåðêè
â îïûòàõ íà ëàáîðàòîðíûõ æèâîòíûõ, à òàêæå, åñëè ýòî íå ïðîòèâîðå÷èò ýòè÷åñêèì ïðèíöèïàì, ñ ïîìîùüþ êëèíè÷åñêèõ èññëåäîâàíèé.
Êëþ÷åâûå ñëîâà: öèòîãåðîíòîëîãèÿ, ãåðîïðîòåêòîðû, êóëüòèâèðóåìûå êëåòêè, “ñòàöèîíàðíîå ñòàðåíèå”, ôåíîìåí Õåéôëèêà, æèçíåñïîñîáíîñòü êëåòîê, çàêîí Ãîìïåðòöà.
Öèòîãåðîíòîëîãèÿ çàíèìàåòñÿ èçó÷åíèåì ìåõàíèçìîâ ñòàðåíèÿ íà êóëüòèâèðóåìûõ êëåòêàõ [1—7].
 íàñòîÿùåå âðåìÿ èìåííî ñ ïîìîùüþ öèòîãåðîíòîëîãè÷åñêèõ ýêñïåðèìåíòîâ äîâîëüíî ÷àñòî ïðîâîäÿòñÿ èññëåäîâàíèÿ ïîòåíöèàëüíûõ ãåðîïðîòåêòîðîâ —
õèìè÷åñêèõ èëè ôèçè÷åñêèõ ôàêòîðîâ, çàìåäëÿþùèõ
ïðîöåññ ñòàðåíèÿ, ò.å. ïðîöåññ óâåëè÷åíèÿ ñ âîçðàñòîì âåðîÿòíîñòè ñìåðòè îðãàíèçìà. Íåîáõîäèìî ïîä÷åðêíóòü, ÷òî, áóäó÷è ÷àñòüþ âñåé ãåðîíòîëîãèè, öèòîãåðîíòîëîãèÿ íå ìîæåò ñóùåñòâîâàòü áåç ñîîòâåòñòâóþùèõ êîððåêòíûõ îáùåãåðîíòîëîãè÷åñêèõ ïîíÿòèé
è îïðåäåëåíèé.
Ê ñîæàëåíèþ, çíà÷èòåëüíî âîçðîñøèé â ïîñëåäíåå âðåìÿ èíòåðåñ ê ýêñïåðèìåíòàëüíî-ãåðîíòîëîãè÷åñêèì èññëåäîâàíèÿì ïðèâåë ê ïàðàäîêñàëüíîé ñèòóàöèè: õîòÿ â ýòîé îáëàñòè ïîÿâëÿåòñÿ âñå áîëüøåå
è áîëüøåå êîëè÷åñòâî ðàáîò, ëèøü íåçíà÷èòåëüíàÿ èõ
÷àñòü äåéñòâèòåëüíî ïîñâÿùåíà èçó÷åíèþ ìåõàíèçìîâ
ñòàðåíèÿ. Íà íàø âçãëÿä, ýòî îïðåäåëÿåòñÿ â ÷èñëå
ïðî÷åãî ñëåäóþùèìè îáñòîÿòåëüñòâàìè.
1. Êàê ïðàâèëî, êëàññè÷åñêîå îïðåäåëåíèå ñòàðåíèÿ êàê ñîâîêóïíîñòè âîçðàñòíûõ èçìåíåíèé, ïðèâîäÿùèõ ê óâåëè÷åíèþ âåðîÿòíîñòè ñìåðòè, èãíîðèðóåòñÿ.
2. Îñíîâíîé àêöåíò äåëàåòñÿ íà óâåëè÷åíèè èëè
óìåíüøåíèè ïðîäîëæèòåëüíîñòè æèçíè, õîòÿ î÷åíü
÷àñòî ýòî íå èìååò íèêàêîãî îòíîøåíèÿ ê ìîäèôèêàöèè ïðîöåññà ñòàðåíèÿ (â ÷àñòíîñòè, âïîëíå óñïåøíî ìîæíî ïðîäëèòü æèçíü íåñòàðåþùèì îðãàíèçìàì;
â òî æå âðåìÿ ñàìî íàëè÷èå ñòàðåíèÿ íå îáÿçàòåëüíî
ñâèäåòåëüñòâóåò î íèçêîì äîëãîëåòèè).
3.  êà÷åñòâå êîíòðîëüíûõ èñïîëüçóþòñÿ æèâîòíûå ñ îïðåäåëåííûìè àíîìàëèÿìè (òèïà ãåíåòè÷åñêèõ çàáîëåâàíèé), òàê ÷òî ëþáîå áëàãîïðèÿòíîå âîçäåéñòâèå íà ñîîòâåòñòâóþùèå ïàòîëîãè÷åñêèå ïðîöåññû âåäåò ê óâåëè÷åíèþ ïðîäîëæèòåëüíîñòè æèçíè.
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4. Ñëèøêîì áîëüøîå çíà÷åíèå ïðèäàåòñÿ óâåëè÷åíèþ èëè óìåíüøåíèþ ñðåäíåé ïðîäîëæèòåëüíîñòè
æèçíè, êîòîðàÿ âî ìíîãîì îïðåäåëÿåòñÿ ôàêòîðàìè,
íèêàê íå ñâÿçàííûìè ñî ñòàðåíèåì.
5. Âñå áîëüøåå êîëè÷åñòâî ãåðîíòîëîãè÷åñêèõ
ýêñïåðèìåíòîâ ïðîâîäèòñÿ íà ìîäåëüíûõ ñèñòåìàõ,
îáåñïå÷èâàþùèõ ëèøü êîñâåííóþ èíôîðìàöèþ î ìåõàíèçìàõ ñòàðåíèÿ, èíòåðïðåòàöèÿ êîòîðîé âî ìíîãîì çàâèñèò îò òîé ôóíäàìåíòàëüíîé êîíöåïöèè,
êîòîðîé ïðèäåðæèâàþòñÿ êîíêðåòíûå èññëåäîâàòåëè.  ÷àñòíîñòè, ýòî êàñàåòñÿ ñëîæèâøåéñÿ ê íàñòîÿùåìó âðåìåíè ñèòóàöèè ñ èñïîëüçîâàíèåì òåðìèíà
“êëåòî÷íîå ñòàðåíèå” (cell/cellular senescence). Èçíà÷àëüíî îí áûë ââåäåí äëÿ îïèñàíèÿ ñîâîêóïíîñòè
ðàçëè÷íûõ íåáëàãîïðèÿòíûõ èçìåíåíèé â íîðìàëüíûõ
êëåòêàõ âñëåäñòâèå èñ÷åðïàíèÿ èìè ïðîëèôåðàòèâíîãî ïîòåíöèàëà [1, 8—10]. Îäíàêî òåïåðü ýòîò òåðìèí, íàïðîòèâ, âñå ÷àùå èñïîëüçóåòñÿ äëÿ îáîçíà÷åíèÿ ÿâëåíèÿ ïîäàâëåíèÿ ïîä âëèÿíèåì ðàçëè÷íûõ
ÄÍÊ-ïîâðåæäàþùèõ ôàêòîðîâ ïðîëèôåðàòèâíîé àêòèâíîñòè êëåòîê (âêëþ÷àÿ è òðàíñôîðìèðîâàííûå),
ñîïðîâîæäàþùåãîñÿ îïðåäåëåííûì êàñêàäîì âíóòðèêëåòî÷íûõ ñîáûòèé [11—13].
6. È, íàêîíåö, òî, ÷òî ìû íàçûâàåì “ïðîáëåìîé
ðåäóêöèîíèçìà”. Ïîäàâëÿþùåå áîëüøèíñòâî ãåðîíòîëîãè÷åñêèõ òåîðèé, ïîÿâèâøèõñÿ â ïîñëåäíèå äåñÿòèëåòèÿ, ñâîäèëè ìåõàíèçìû êàê “íîðìàëüíîãî”,
òàê è óñêîðåííîãî èëè çàìåäëåííîãî ñòàðåíèÿ ìíîãîêëåòî÷íûõ îðãàíèçìîâ ê îïðåäåëåííûì ìàêðîìîëåêóëÿðíûì èçìåíåíèÿì (íå ïðèíöèïèàëüíî, ñòîõàñòè÷åñêèì èëè çàïðîãðàììèðîâàííûì) â ñîñòàâëÿþùèõ
èõ êëåòêàõ. Ýòî ïðèâåëî ê ïîÿâëåíèþ áîëüøîãî êîëè÷åñòâà ìîäåëüíûõ ñèñòåì, îáåñïå÷èâàþùèõ èçó÷åíèå “âîçðàñòíûõ” èçìåíåíèé â êëåòêàõ, îñâîáîæäåííûõ îò “îðãàíèçìåííîãî øóìà”, ñâÿçàííîãî ñ
ôóíêöèîíèðîâàíèåì íåéðîãóìîðàëüíîé è íåðâíîé
ñèñòåì. Òàêîé ðåäóêöèîíèçì â ýêñïåðèìåíòàëüíîé ãåðîíòîëîãèè (“âñå îïðåäåëÿåòñÿ íåáëàãîïðèÿòíûìè èçìåíåíèÿìè â îòäåëüíûõ êëåòêàõ”) ñûãðàë ñâîþ ðîëü,
â ÷àñòíîñòè â ðàçðàáîòêå ìîäåëè Õåéôëèêà, à òàêæå
íåêîòîðûõ ìîäåëåé, èñïîëüçóåìûõ â íàøåé ëàáîðàòîðèè (ìîäåëü “ñòàöèîíàðíîãî ñòàðåíèÿ”, êëåòî÷íîêèíåòè÷åñêàÿ ìîäåëü äëÿ èñïûòàíèÿ ãåðîïðîòåêòîðîâ
è ãåðîïðîìîòîðîâ, îöåíêà ñïîñîáíîñòè êëåòîê ê îáðàçîâàíèþ êîëîíèé).
Ê ñîæàëåíèþ, ìîäåëü, îñíîâàííàÿ íà ôåíîìåíå Õåéôëèêà (“ñòàðåíèå in vitro”), êàê óæå íåîäíîêðàòíî îòìå÷àëîñü ðàíåå [7, 14—21], ïî-âèäèìîìó,
íàïðÿìóþ íå ñâÿçàíà ñ ìåõàíèçìàìè ñòàðåíèÿ. Èíà÷å
ãîâîðÿ, ìû íå ìîæåì äîñêîíàëüíî îáúÿñíèòü, ïî÷åìó ìû ñòàðååì, ñ ïîìîùüþ ôåíîìåíà îãðàíè÷åííîãî
ìèòîòè÷åñêîãî ïîòåíöèàëà íîðìàëüíûõ êëåòîê, êîòîðûé ïðàêòè÷åñêè íèêîãäà íå èñïîëüçóåòñÿ äî êîíöà in vivo. Ïðàâäà, ìû òåïåðü, áëàãîäàðÿ êîíöåïöèè
ìàðãèíîòîìèè À.Ì. Îëîâíèêîâà [22—24], ïî êðàéíåé
ìåðå çíàåì, êàêèì îáðàçîì äàííûé ôåíîìåí ðåàëèçóåòñÿ â êëåòêàõ.
Íå èñêëþ÷åíî, ÷òî ïðè óâåëè÷åíèè ìàêñèìàëüíîé ïðîäîëæèòåëüíîñòè æèçíè ÷åëîâåêà â íåñêîëüêî
ðàç íåêîòîðûå ïîïóëÿöèè êëåòîê â íàøåì îðãàíèçìå
âñå æå èñ÷åðïàëè áû ñâîé ìèòîòè÷åñêèé ïîòåíöèàë
è òîãäà “ëèìèò Õåéôëèêà” ìîã áû ïðèâåñòè êî “âòîðîé âîëíå” ñòàðåíèÿ, íî ïîêà ýòîãî íå ñëó÷èëîñü.
Íåîáõîäèìî, âïðî÷åì, óïîìÿíóòü, ÷òî íåêîòîðûå èññëåäîâàòåëè (ñì., â ÷àñòíîñòè, [25]) ïðîäîëæàþò ñ÷èòàòü óêîðî÷åíèå òåëîìåð â êëåòêàõ êëþ÷åâûì ìåõàíèçìîì ñòàðåíèÿ.
 îòëè÷èå îò ìîäåëè Õåéôëèêà, îñíîâàííîé íà
öåëîì ðÿäå êîððåëÿöèé [4, 18], èñïîëüçóåìàÿ â íàøåé ëàáîðàòîðèè ìîäåëü “ñòàöèîíàðíîãî ñòàðåíèÿ”
(íàêîïëåíèå “âîçðàñòíûõ” ïîâðåæäåíèé â êóëüòèâèðóåìûõ êëåòêàõ, ïðîëèôåðàöèÿ êîòîðûõ çàòîðìîæåíà êàêèì-ëèáî ñïîñîáîì, ëó÷øå âñåãî — ñ ïîìîùüþ
êîíòàêòíîãî òîðìîæåíèÿ) ïðåäïîëàãàåò “ñóùíîñòíîå” ñõîäñòâî ïðîöåññîâ â äàííîé ìîäåëüíîé ñèñòåìå è â ñòàðåþùåì ìíîãîêëåòî÷íîì îðãàíèçìå (2, 4,
26—31). Ôàêòè÷åñêè ýòî ñõîäñòâî íàïðÿìóþ âûòåêàåò èç íàøåé êîíöåïöèè îãðàíè÷åíèÿ êëåòî÷íîé
ïðîëèôåðàöèè êàê îñíîâíîãî ìåõàíèçìà íàêîïëåíèÿ
ñ âîçðàñòîì ìàêðîìîëåêóëÿðíûõ äåôåêòîâ â êëåòêàõ ìíîãîêëåòî÷íûõ îðãàíèçìîâ [2, 7, 17, 18]. Áîëåå
òîãî, íàøè íåäàâíèå èññëåäîâàíèÿ ïîçâîëèëè ñäåëàòü
âûâîä, ÷òî êóëüòèâèðóåìûå êëåòêè â ñòàöèîíàðíîé
ôàçå ðîñòà äåéñòâèòåëüíî “ñòàðåþò ïî Ãîìïåðòöó”
(ðèñóíîê), ò.å. âåðîÿòíîñòü èõ ãèáåëè ýêñïîíåíöèàëüíî ðàñòåò ñî âðåìåíåì â ñîîòâåòñòâèè ñ çàêîíîì
Ãîìïåðòöà [7, 18]. Ìåæäó ïðî÷èì, ñõîäíûå äàííûå
áûëè â ñâîå âðåìÿ ïîëó÷åíû äàæå íà ñóñïåíçèîííîé
êóëüòóðå Acholeplasma laidlawii [32], íà “ñòàöèîíàðíîå ñòàðåíèå” êîòîðîé, êñòàòè, íàì óäàëîñü óñïåøíî ïîâëèÿòü ñ ïîìîùüþ ãåðîïðîòåêòîðà-àíòèîêñèäàíòà õëîðãèäðàòà 2-ýòèë-6-ìåòèë-3-îêñèïèðèäèíà [33].
Õîòåëîñü áû ïîä÷åðêíóòü, ÷òî êðèâûå, ïðåäñòàâëåííûå, íà ðèñóíêå, áûëè ïîëó÷åíû íà òðàíñôîðìèðîâàííûõ êëåòêàõ. Åñëè êóëüòèâèðóåìûì ðàêîâûì êëåòêàì ïîçâîëÿòü íåîãðàíè÷åííî ðàçìíîæàòüñÿ, òî êîíêðåòíàÿ ëèíèÿ (íî íå îòäåëüíûå êëåòêè!) áóäåò “áåññìåðòíîé”. Ñêàæåì, èçâåñòíàÿ ëèíèÿ êëåòîê HeLa
ïîääåðæèâàåòñÿ â ñîòíÿõ ëàáîðàòîðèé óæå íà ïðîòÿæåíèè áîëåå ÷åì 60 ëåò. Îäíàêî ïðè îãðàíè÷åíèè
Êðèâàÿ âûæèâàíèÿ ñòàöèîíàðíîé êóëüòóðû òðàíñôîðìèðîâàííûõ êëåòîê êèòàéñêîãî õîìÿ÷êà. 1 — ýêñïåðèìåíòàëüíûå òî÷êè;
2 — àïïðîêñèìàöèÿ äàííûõ óðàâíåíèåì Ãîìïåðòöà; 3 — èçìåíåíèå ñèëû ñìåðòíîñòè ñî âðåìåíåì
ÂÅÑÒÍ. ÌÎÑÊ. ÓÍ-ÒÀ. ÑÅÐ. 16. ÁÈÎËÎÃÈß. 2014. ¹ 1
15
ðîñòà òàêîé êóëüòóðû òåì èëè èíûì ôèçèîëîãè÷åñêèì (íå âûçûâàþùèì ãèáåëü êëåòîê) ñïîñîáîì â åå
êëåòêàõ íà÷èíàþò íàêàïëèâàòüñÿ ðàçëè÷íûå äåôåêòû íà ñàìûõ ðàçíûõ óðîâíÿõ, â ðåçóëüòàòå ÷åãî âåðîÿòíîñòü èõ ñìåðòè ïîâûøàåòñÿ, ò.å. îíè ðåàëüíî ñòàðåþò (áåç êàâû÷åê) [34].
Âïðî÷åì, íåîáõîäèìî çàìåòèòü, ÷òî ìû âñåãäà
äîëæíû (îñíîâûâàÿñü íà ïðåäñòàâëåíèÿõ òåîðèè íàäåæíîñòè) èìåòü â âèäó ñëåäóþùåå îáñòîÿòåëüñòâî:
ñòàðåþùèé ìíîãîêëåòî÷íûé îðãàíèçì ñîâñåì íå îáÿçàòåëüíî äîëæåí ñîñòîÿòü èç ñòàðåþùèõ êëåòîê. Îíè
âïîëíå ìîãóò ïðîñòî âûìèðàòü “ïî ýêñïîíåíòå”, ò.å.
áåç ñòàðåíèÿ (êàê â ñëó÷àå ðàäèîàêòèâíîãî ðàñïàäà).
Ê ñîæàëåíèþ, ñíÿòèå êðèâûõ âûæèâàíèÿ êóëüòèâèðóåìûõ êëåòîê ñîïðÿæåíî ñ îïðåäåëåííûìè ìåòîäè÷åñêèìè è ìåòîäîëîãè÷åñêèìè ïðîáëåìàìè, êîòîðûå íåëüçÿ íå óïîìÿíóòü. Âî-ïåðâûõ, êëåòêè ìîãóò
äåëèòüñÿ, ÷òî íàðóøàåò öåëîñòíîñòü êîãîðòû. Âî-âòîðûõ, êîððåêòíî çàôèêñèðîâàòü ìîìåíò êëåòî÷íîé ãèáåëè íå òàê ïðîñòî.  íàñòîÿùåå âðåìÿ ñóùåñòâóåò
î÷åíü áîëüøîå êîëè÷åñòâî ñîîòâåòñòâóþùèõ òàê íàçûâàåìûõ “çîíäîâ”, ïðåäíàçíà÷åííûõ äëÿ ýòèõ öåëåé,
îäíàêî îíè äàþò äîâîëüíî ñèëüíî ðàçëè÷àþùèåñÿ
ðåçóëüòàòû. Èíà÷å ãîâîðÿ, äîñòàòî÷íî ÷àñòî îäíà è
òà æå êëåòêà îïðåäåëÿåòñÿ êàê æèâàÿ ñ ïîìîùüþ
îäíîãî òåñòà è êàê ìåðòâàÿ — ñ ïîìîùüþ äðóãîãî.
Ìåòîä îöåíêè ñïîñîáíîñòè êëåòîê ê îáðàçîâàíèþ
êîëîíèé [35, 36] ýôôåêòèâåí òîëüêî äëÿ ïðîëèôåðèðóþùèõ êëåòîê (òàê ÷òî òàêèì ñïîñîáîì íåëüçÿ,
íàïðèìåð, îöåíèòü æèçíåñïîñîáíîñòü íåéðîíîâ èëè
êàðäèîìèîöèòîâ). ×òî æå êàñàåòñÿ “ñòàöèîíàðíî ñòàðûõ” êóëüòèâèðóåìûõ êëåòîê, òî ìíîãèå èç íèõ ìîãóò ïðîñòî íå ïåðåæèòü äîñòàòî÷íî òðàâìàòè÷íóþ ïðîöåäóðó ñíÿòèÿ ñ ïîâåðõíîñòè ðîñòà è ïîñëåäóþùåå
êëîíèðîâàíèå.
Íàøè ìíîãî÷èñëåííûå ýêñïåðèìåíòû ïîçâîëèëè ïðîäåìîíñòðèðîâàòü, ÷òî â ðàìêàõ íàøåé ìîäåëüíîé ñèñòåìû â êëåòêàõ äåéñòâèòåëüíî ïðîèñõîäÿò èçìåíåíèÿ, ñõîäíûå ñ èçìåíåíèÿìè êëåòîê ñòàðåþùèõ
ìíîãîêëåòî÷íûõ îðãàíèçìîâ: íàêàïëèâàþòñÿ îäíîíèòåâûå ðàçðûâû ÄÍÊ è ñøèâêè ÄÍÊ—áåëîê, èäåò
äåìåòèëèðîâàíèå ÄÍÊ, èçìåíÿåòñÿ óðîâåíü ñïîíòàííûõ ñåñòðèíñêèõ õðîìàòèäíûõ îáìåíîâ, âîçíèêàþò äåôåêòû ñòðóêòóðû êëåòî÷íîãî ÿäðà, èçìåíÿåòñÿ
ïëàçìàòè÷åñêàÿ ìåìáðàíà, çàìåäëÿåòñÿ ñòèìóëèðîâàííàÿ ìèòîãåíàìè ïðîëèôåðàöèÿ êëåòîê, óõóäøàåòñÿ èõ ñïîñîáíîñòü îáðàçîâûâàòü êîëîíèè, ìåíÿåòñÿ äåàëêèëàçíàÿ àêòèâíîñòü öèòîõðîìà P-450, â ÄÍÊ
íàêàïëèâàåòñÿ èçâåñòíûé áèîìàðêåð ñòàðåíèÿ 8-îêñî-2¢-äåõîêñèãóàíîçèí, óâåëè÷èâàåòñÿ ÷èñëî êëåòîê
ñ áåòà-ãàëàêòîçèäàçîé pH 6,0 (íàèáîëåå ÷àñòî èñïîëüçóåìûé áèîìàðêåð êëåòî÷íîãî ñòàðåíèÿ), èäåò ïðîöåññ èíãèáèðîâàíèÿ ïîëè(ADP-ðèáîçèë)èðîâàíèÿ áåëêîâ õðîìàòèíà è äð. [2, 7, 37—45].
Õîòåëîñü áû ïîä÷åðêíóòü, ÷òî òàêèå ýêñïåðèìåíòû ìîæíî ïðîâîäèòü íà êëåòêàõ ñàìîé ðàçíîé
ïðèðîäû, âêëþ÷àÿ áàêòåðèè, äðîææè (èìåííî íà íèõ
èññëåäîâàíèÿ ôåíîìåíà “ñòàöèîíàðíîãî ñòàðåíèÿ”
ïðîâîäÿòñÿ â íàñòîÿùåå âðåìÿ íàèáîëåå ÷àñòî), ðàñòèòåëüíûå êëåòêè, ìèêîïëàçìû è äð. Ýòî îáñòîÿòåëüñòâî îáåñïå÷èâàåò ýâîëþöèîííûé ïîäõîä ê àíàëèçó
ïîëó÷àåìûõ ðåçóëüòàòîâ [46]. Êðîìå òîãî, ìû ôèêñèðóåì “âîçðàñòíûå” èçìåíåíèÿ â êëåòêàõ ñòàöèîíàðíûõ êóëüòóð äîâîëüíî áûñòðî — êàê ïðàâèëî, óæå
÷åðåç 2—3 íåäåëè ïîñëå íà÷àëà ýêñïåðèìåíòà.
Âàæíî òàêæå, ÷òî, åñëè ìîäåëü Õåéôëèêà äåëàåò
äîâîëüíî òðóäíûìè êîððåêòíûå ïîâòîðíûå ýêñïåðèìåíòû íà îäíîì è òîì æå øòàììå, èáî êëåòêè âñå
âðåìÿ èçìåíÿþòñÿ îò ïàññàæà ê ïàññàæó (“íåëüçÿ
âîéòè äâàæäû â îäíó ðåêó”), òî ìîäåëü “ñòàöèîíàðíîãî ñòàðåíèÿ” ïîçâîëÿåò ðàáîòàòü, êàê óæå îòìå÷àëîñü âûøå, íà îáëàäàþùèõ íåîãðàíè÷åííûì ìèòîòè÷åñêèì ïîòåíöèàëîì òðàíñôîðìèðîâàííûõ (èëè
íîðìàëüíûõ, íî èììîðòàëèçîâàííûõ) êëåòêàõ æèâîòíûõ èëè ÷åëîâåêà, òàê ÷òî ìíîãîêðàòíîå âîñïðîèçâåäåíèå ñîîòâåòñòâóþùèõ ýêñïåðèìåíòîâ óæå íå ÿâëÿåòñÿ ïðîáëåìîé [34].
Âñå âûøåñêàçàííîå ïîçâîëèëî íàì ïðåäïîëîæèòü,
÷òî èñïîëüçîâàíèå ìîäåëè “ñòàöèîíàðíîãî ñòàðåíèÿ”
(“stationary phase aging” â àíãëîÿçû÷íîé ëèòåðàòóðå)
ìîæåò ÿâëÿòüñÿ ýôôåêòèâíûì ïîäõîäîì ê òåñòèðîâàíèþ ïîòåíöèàëüíîé ñïîñîáíîñòè ðàçëè÷íûõ ïðåïàðàòîâ èëè èõ êîìáèíàöèé óñêîðÿòü èëè çàìåäëÿòü
ñòàðåíèå — êîíå÷íî, åñëè èõ äåéñòâèå ðåàëèçóåòñÿ
òîëüêî íà êëåòî÷íîì óðîâíå.
Âïðî÷åì, â ïîñëåäíåå âðåìÿ ó íàñ ñëîæèëîñü âïå÷àòëåíèå, ÷òî äàæå äàííûå, ïîëó÷åííûå íà òàêèõ “ñóùíîñòíûõ” ìîäåëÿõ, èñïîëüçóþùèõ êóëüòèâèðóåìûå
êëåòêè, íå ìîãóò áûòü íàïðÿìóþ ïåðåíåñåíû íà ñèòóàöèþ â öåëîì îðãàíèçìå [7, 18, 30, 31]. Íàøè ñîáñòâåííûå öèòîãåðîíòîëîãè÷åñêèå èñïûòàíèÿ ðàçëè÷íûõ
ãåðîïðîòåêòîðîâ ñ ïîìîùüþ ìîäåëè “ñòàöèîíàðíîãî
ñòàðåíèÿ”, êëåòî÷íî-êèíåòè÷åñêîé ìîäåëè [47] è ìåòîäà îöåíêè ñïîñîáíîñòè ê êîëîíèåîáðàçîâàíèþ [35]
ïîêàçàëè, ÷òî äîñòàòî÷íî ÷àñòî èçó÷àåìûå ôàêòîðû
íå îêàçûâàþò áëàãîïðèÿòíîãî äåéñòâèÿ íà æèçíåñïîñîáíîñòü êóëüòèâèðóåìûõ êëåòîê, õîòÿ è ïðîäëåâàþò æèçíü ýêñïåðèìåíòàëüíûì æèâîòíûì, à òàêæå
óëó÷øàþò ñàìî÷óâñòâèå ëþäåé. Ýòî ïîçâîëèëî íàì
ïðåäïîëîæèòü, ÷òî âî ìíîãèõ ñëó÷àÿõ äåéñòâèå ãåðîïðîòåêòîðà ïðîÿâëÿåòñÿ òîëüêî íà îðãàíèçìåííîì
óðîâíå (âîçìîæíî, ïðîñòî çà ñ÷åò âêëþ÷åíèÿ/âûêëþ÷åíèÿ íåêîòîðûõ áèîõèìè÷åñêèõ èëè íåéðîôèçèîëîãè÷åñêèõ ïðîöåññîâ) è íå ñâîäèòñÿ òîëüêî ê óâåëè÷åíèþ æèçíåñïîñîáíîñòè îòäåëüíûõ êëåòîê îðãàíèçìà.
Î÷åâèäíî, ÷òî ñõîäíûé âûâîä ìîæåò áûòü ñäåëàí è
äëÿ ãåðîïðîìîòîðîâ (ôàêòîðîâ, óñêîðÿþùèõ ñòàðåíèå îðãàíèçìà). Òàêèì îáðàçîì, èçáàâèâøèñü â ýêñïåðèìåíòàõ íà êóëüòèâèðóåìûõ êëåòêàõ îò âëèÿíèÿ
ýíäîêðèííîé è öåíòðàëüíîé íåðâíîé ñèñòåì (÷òî,
ñîáñòâåííî, è áûëî îñíîâíîé öåëüþ öèòîãåðîíòîëîãîâ, íà÷èíàÿ åùå ñ èññëåäîâàíèé Àëåêñèñà Êàððåëÿ
[48, 49]), ìû, âîçìîæíî, ñäåëàëè ñåðüåçíóþ îøèáêó. Ñóäÿ ïî âñåìó, äàííûå, ïîëó÷åííûå â öèòîãåðîíòîëîãè÷åñêèõ ýêñïåðèìåíòàõ, äîëæíû áûòü òùàòåëüíî ïåðåïðîâåðåíû íà ëàáîðàòîðíûõ æèâîòíûõ
16
ÂÅÑÒÍ. ÌÎÑÊ. ÓÍ-ÒÀ. ÑÅÐ. 16. ÁÈÎËÎÃÈß. 2014. ¹ 1
è, åñëè ýòî íå ïðîòèâîðå÷èò ýòè÷åñêèì ïðèíöèïàì,
äàæå íà ëþäÿõ. Ê ñîæàëåíèþ, ýòî ðåçêî ïîíèçèò
íàøè øàíñû íà áûñòðûé ïðîðûâ â îáëàñòè èçó÷å-
íèÿ âîçìîæíîñòåé çàìåäëåíèÿ ïðîöåññà ñòàðåíèÿ, íî
çàòî çíà÷èòåëüíî óâåëè÷èò íàäåæíîñòü ïîëó÷àåìûõ
ðåçóëüòàòîâ.
ÑÏÈÑÎÊ ËÈÒÅÐÀÒÓÐÛ
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2. Õîõëîâ À.Í. Ïðîëèôåðàöèÿ è ñòàðåíèå // Èòîãè íàóêè è òåõíèêè ÂÈÍÈÒÈ ÀÍ ÑÑÑÐ, ñåðèÿ “Îáùèå ïðîáëåìû ôèçèêî-õèìè÷åñêîé áèîëîãèè”. Ò. 9. Ì.: ÂÈÍÈÒÈ,
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3. Õîõëîâ À.Í. Èòîãè è ïåðñïåêòèâû öèòîãåðîíòîëîãè÷åñêèõ èññëåäîâàíèé íà ñîâðåìåííîì ýòàïå // Öèòîëîãèÿ. 2002. Ò. 44. ¹ 12. Ñ. 1143—1148.
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5. Õîõëîâ À.Í. Ãåðîíòîëîãè÷åñêèå èññëåäîâàíèÿ íà
êëåòî÷íûõ êóëüòóðàõ: îò îðãàíèçìà ê êëåòêå è îáðàòíî // Ïðîáë. ñòàðåíèÿ è äîëãîëåòèÿ. 2008. Ò. 17. ¹ 4.
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6. Õîõëîâ À.Í. Òåñòèðîâàíèå ãåðîïðîòåêòîðîâ â ýêñïåðèìåíòàõ íà êëåòî÷íûõ êóëüòóðàõ: çà è ïðîòèâ // Ïðîáë.
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â ïîíèìàíèè ñòàðåíèÿ ÷åëîâåêà // Êëèí. ãåðîíòîë. 2005.
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22. Îëîâíèêîâ À.Ì. Ïðèíöèï ìàðãèíîòîìèè â ìàòðè÷íîì ñèíòåçå ïîëèíóêëåîòèäîâ // Äîêë. ÀÍ ÑÑÑÐ. 1971.
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the seeming contradictions in the telomere theory of aging //
Mech. Ageing Dev. 2001. Vol. 122. N 13. P. 1361—1365.
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27. Khokhlov A.N. Stationary cell cultures as a tool for
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28. Khokhlov A.N. Cell proliferation restriction: is it the
primary cause of aging? // Ann. N.Y. Acad. Sci. 1998. Vol. 854.
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29. Akimov S.S., Khokhlov A.N. Study of “stationary
phase aging” of cultured cells under various types of proliferation restriction // Ann. N.Y. Acad. Sci. 1998. Vol. 854.
P. 520.
30. Alinkina E.S., Vorobyova A.K., Misharina T.A., Fatkullina L.D., Burlakova E.B., Khokhlov A.N. Cytogerontological studies of biological activity of oregano essential oil //
Moscow Univ. Biol. Sci. Bull. 2012. Vol. 67. N 2. P. 52—57.
31. Yablonskaya O.I., Ryndina T.S., Voeikov V.L., Khokhlov A.N. A paradoxical effect of hydrated C60-fullerene at
an ultralow concentration on the viability and aging of cultured
Chinese hamster cells // Moscow Univ. Biol. Sci. Bull. 2013.
Vol. 68. N 2. P. 63—68.
32. Kapitanov A.B., Aksenov M.Y. Ageing of procaryotes. Acholeplasma laidlawii as an object for cell ageing studies: a brief note // Mech. Ageing Dev. 1990. Vol. 54. N 3.
P. 249—258.
33. Õîõëîâ À.Í., Óøàêîâ Â.Ë., Êàïèòàíîâ À.Á., Íàäæàðÿí Ò.Ë. Âëèÿíèå ãåðîïðîòåêòîðà õëîðãèäðàòà 2-ýòèë6-ìåòèë-3-îêñèïèðèäèíà íà ïðîëèôåðàöèþ êëåòîê Acholeplasma laidlawii // Äîêë. ÀÍ ÑÑÑÐ. 1984. Ò. 274. ¹ 4.
Ñ. 930—933.
34. Khokhlov A.N. Can cancer cells age? Stationary cell
culture approach to the problem solution // Visualizing of
senescent cells in vitro and in vivo. Programme and abst-
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P. 48—49.
35. Khokhlov A.N., Prokhorov L.Yu., Ivanov A.S., Archakov A.I. Effects of cholesterol- or 7-ketocholesterol-containing
liposomes on colony-forming ability of cultured cells // FEBS
Lett. 1991. Vol. 290. N 1—2. P. 171—172.
36. Maier A.B., Maier I.L., van Heemst D., Westendorp R.G.J. Colony formation and colony size do not reflect
the onset of replicative senescence in human fibroblasts //
J. Gerontol. A Biol. Sci. Med. Sci. 2008. Vol. 63. N 7.
P. 655—659.
37. Õîõëîâ À.Í., ×èðêîâà Å.Þ., Íàäæàðÿí Ò.Ë. Äåãðàäàöèÿ ÄÍÊ â ïîêîÿùèõñÿ êóëüòèâèðóåìûõ êëåòêàõ êèòàéñêîãî õîìÿ÷êà // Öèòîëîãèÿ. 1984. Ò. 26. ¹ 8. Ñ. 965—968.
38. Õîõëîâ À.Í., ×èðêîâà Å.Þ., ×åáîòàðåâ À.Í. Èçìåíåíèÿ óðîâíÿ ñåñòðèíñêèõ õðîìàòèäíûõ îáìåíîâ â êóëüòèâèðóåìûõ êëåòêàõ êèòàéñêîãî õîìÿ÷êà ïðè îãðàíè÷åíèè
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Ïîñòóïèëà â ðåäàêöèþ
01.09.13
TESTING OF ANTI-AGING DRUGS IN EXPERIMENTS
ON CELL CULTURES: CHOOSING THE CORRECT MODEL SYSTEM
A.N. Khokhlov, A.A. Klebanov, A.F. Karmushakov, G.A. Shilovsky,
M.M. Nasonov, G.V. Morgunova
The authors think that cytogerontological models similar to the Hayflick’s model, though very
useful for experimental gerontology, are based on some correlations only and not related necessarily
to the gist of the aging phenomenon. If the rationale of the “Hayflick phenomenon” is used, we
cannot explain why we age. In contrast, the “stationary phase aging” model is obviously a “gist”
model, because it is based on the hypothesis that the main cause of both various intracellular “age”
changes in the cells of stationary cultures and similar changes in the cells of multicellular aging organism is the cell proliferation restriction. The model is suitable for experiments on wide spectrum of various cultured cells including normal and transformed animal and human cells, plant cells,
bacteria, yeasts, mycoplasmas, etc. Results of the relevant investigations showed that the cells in the
“stationary phase aging” model died out in accordance with the Gompertz law that describes exponential increase of the death probability with time. It is assumed that the “stationary phase aging”
model can provide an effective approach to testing of various anti-aging and pro-aging factors in cytogerontological experiments. However, the authors emphasize that even the results of such studies
sometimes do not coincide with the data obtained in vivo and, because of this, cannot be considered
as final. They should be double-checked on laboratory animals and, if it complies with ethical regulations, even on humans.
Key words: cytogerontology, anti-aging factors, cultured cells, “stationary phase aging”, Hayflick
phenomenon, cell viability, Gompertz law.
18
ÂÅÑÒÍ. ÌÎÑÊ. ÓÍ-ÒÀ. ÑÅÐ. 16. ÁÈÎËÎÃÈß. 2014. ¹ 1
Ñâåäåíèÿ îá àâòîðàõ
Õîõëîâ Àëåêñàíäð Íèêîëàåâè÷ — äîêò. áèîë. íàóê, çàâ. ñåêòîðîì ýâîëþöèîííîé öèòîãåðîíòîëîãèè
áèîëîãè÷åñêîãî ôàêóëüòåòà ÌÃÓ. Òåë.: 8-495-939-15-90; e-mail: [email protected]
Êëåáàíîâ Àëåêñàíäð Àëåêñàíäðîâè÷ — íàó÷. ñîòð. ñåêòîðà ýâîëþöèîííîé öèòîãåðîíòîëîãèè áèîëîãè÷åñêîãî ôàêóëüòåòà ÌÃÓ. Òåë.: 8-495-939-15-90; e-mail: [email protected]
Êàðìóøàêîâ Àçàð Ôàòôóëîâè÷ — èíæåíåð ñåêòîðà ýâîëþöèîííîé öèòîãåðîíòîëîãèè áèîëîãè÷åñêîãî ôàêóëüòåòà ÌÃÓ. Òåë.: 8-495-939-15-90; e-mail: [email protected]
Øèëîâñêèé Ãðèãîðèé Àëåêñàíäðîâè÷ — èíæåíåð-ëàáîðàíò êàôåäðû ãåíåòèêè áèîëîãè÷åñêîãî ôàêóëüòåòà ÌÃÓ. Òåë.: 8-495-939-15-90; e-mail: [email protected]
Íàñîíîâ Ìàòâåé Ìèõàéëîâè÷ — ñòóäåíò-äèïëîìíèê ñåêòîðà ýâîëþöèîííîé öèòîãåðîíòîëîãèè áèîëîãè÷åñêîãî ôàêóëüòåòà ÌÃÓ. Òåë.: 8-495-939-15-90; e-mail: [email protected]
Ìîðãóíîâà Ãàëèíà Âàñèëüåâíà — àñïèðàíòêà ñåêòîðà ýâîëþöèîííîé öèòîãåðîíòîëîãèè áèîëîãè÷åñêîãî ôàêóëüòåòà ÌÃÓ. Òåë.: 8-495-939-15-90; e-mail: [email protected]
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