l208S Am J C/in Nuir l992;55:l208S-14S. Printed in USA. © 1992 American Society for Clinical Nutrition Apoptosis-programmed cell death: a role in the aging process?13 Daniela Monti, Leonarda Troiano, Franco Tropea, Emanuela Grassilli, Andrea Cossarizza, Daniela Barozzi, Maria Claudia Pelloni, Maria Grazia Tamassia, Giorgio Bellomo, and Claudio Franceschi ABSTRACT Cells continuously exposed to genotoxic agents, such as oxygen free radicals (OFRs), deeply involved in the aging process use a variety of cellular defense mechanisms. These defense mechanisms include DNA repair enzymes, an- tioxidants, poly(ADP-ribosyl)polymerase (pADPRP), and stress proteins and they constitute an integrated network. An age-re- lated failure of the efficiency of this network can affect cell pro- liferation and cell death, two phenomena tightly linked and reg- ulated. Recent data from our laboratory on the role of DNA damage and pADPRP activation and on the type of cell death induced by OFRs in human lymphocytes are reviewed. In vitro and in vivo data on possible strategies to reduce oxidative stress in lymphocytes from normal and Down syndrome subjects, by using natural compounds and trace elements, are presented. They indicate that nicotinamide and L-carnitine protect human cells from OFR-induced damage and suggest that they are possible candidates as antiaging substances. Am J C/in Nuir l992;55: 12085-145. KEY WORDS Aging, apoptosis, cell death, poly(ADP-n- bosyl)polymerase, oxygen free radicals, carnitine, 3-aminobenz- amide, zinc Introduction Aging is probably the result of genetic and environmental factors. We assume that the continuous exposure to endogenous and exogenous damaging agents play a role in this process. In- deed, cells have to cope with the damage provoked by heat, radiations, glucose, and oxygen free radicals (OFRs), among others. These last compounds are normally produced in the course of several biochemical reactions during cellular metab- olism. More than 30 years ago Harman (I) proposed “the free radicals theory ofaging.” According to this theory, a major role has to be ascribed to reactive oxygen species in aging and se- nescence. Pros and cons of this theory have been reviewed (2, 3). The usual approach to test this hypothesis has been that of correlating the concentration or the activity of a single antiox- idant with aging and/or longevity in a single or a few organs or cell type in a given species. In our opinion, this approach is misleading and suffers from a theoretical weakness. Recently, we argued that the antioxidant defense mechanisms, either en- zymatic or nonenzymatic, must be considered all together be- cause they are involved in complex redox reactions (4). Indeed, OFRs have many targets, including plasma membrane, organ- dIes, proteins, nucleic acids, etc. As a consequence, a variety of defense mechanisms other than antioxidants are triggered by oxidative stress. We have proposed that these mechanisms con- stitute a network ofcellular defense, depicted in Figure 1, which is ofcntical importance for aging and longevity (4). It is usually taken for granted that oxidative stress increases with age and that the efficiency ofantioxidant mechanisms declines with age. However, the data available are scanty and contradictory, par- ticularly as far as humans are concerned. The situation is prob- ably much more complex. A balance between production and processing ofOFRs is continuously taking place (Fig 2) and the age-related derangement may be the consequence of different possibilities as shown in Table 1 . Moreover, we still do not know which is the most important type of damage(s) and the critical cellular target(s) of OFRs. As illustrated in Figure 1, an integral part of our hypothesis is that an age-related derangement ofthe efficiency ofthe network may disturb the subtle and critical equilibrium between cell pro- liferation and cell death that appears to be present in most of the cells (4). In this review we first try to answer questions regarding the role of DNA damage and poly(ADP-ribosyl)polymerase (pADPRP, EC 2.4.2.30) activation in mediating the damage caused by OFRs, and the type of cell death induced by OFRs in human cells. Then, we present data obtained in vitro and in vivo on possible strategies to reduce oxidative stress and protect human cells from the damage caused by OFRs by using natural compounds and nutrients. Role of pADPRP in OFR-damaged human cells pADPRP is a nuclear enzyme activated by single and double DNA strand breaks, which synthesizes ADP-ribose homopoly- I From the Istituto di Patologia Generale, Universit#{225}degli Studi di Modena, Modena and the Clinica Medica I, Universit#{226} degli Studi di Pavia, Policlinico S Matteo, Pavia, Italy. 2 Supported by Murst 40% and 60%; Sigma Tau, Pomezia (Roma); Italian Association for Research on Cancer (AIRC); and Consiglio Na- zionale delle Ricerche, Progetto Finalizzato “Invecchiamento” e Progetto Strategico “Network per la Raccolta di Matenale Biologico per Studi di Biologia Molecolare del Sistema Nervoso.” EG is a recipient ofan AIRC fellowship and DB is a recipient ofa Sigma Tau fellowship. 3 Address reprint requests to C Franceschi, Istituto di Patologia Oen- erale, Universit#{225}di Modena, Via Campi 287, Modena, Italy. by guest on June 1, 2011 www.ajcn.org Downloaded from