Abstract
This study was performed to clarify the transfer and final end of lipofuscin substances that have been formed in cardiomyocytes. The hearts of BALB/c mice were obtained for resin embedding and ultra-thin sectioning. The specimens were observed under a transmission electron microscope, and the images were acquired using an XR401 side-insertion device. Lipofuscin granules are found abundantly in myocardial cells. Cardiomyocytes can excrete lipofuscin granules into the myocardial interstitium using capsule-like protrusions that are formed on the sarcolemma. These granules enter the myocardial interstitium and can be de-aggregated to form membrane-like garbage, which can pass from the myocardial stroma into the lumen of the vessel through its walls. Smaller lipofuscin granules can pass through the walls of the vessels and enter the blood vessel lumen through the capillary endothelial cells. When the extended cytoplasmic end of macrophages and fibroblasts fuse with the endothelial cells, the lipofuscin granules or clumps in the myocardial interstitium are transported to the capillary walls, and then, are released into the lumen of the blood vessel by the endothelial cells. The myocardial tissues of mice may have the ability to eliminate the lipofuscin produced in the cardiomyocytes into the myocardial blood circulation.
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INTRODUCTION
It is well known that one of most important research areas in in vivo anti-aging intervention is to discover objective evaluation indicators. The content of lipofuscin in organs is an important indicator for assessing the aging status. Lipofuscin is a yellowish-brown pigment composed of highly oxidized proteins, lipids, and metals. Lipofuscin is widely observed in post-mitotic cells, especially in cells with long life spans such as neurons and cardiomyocytes [8, 11]. Lipofuscin is often known as the “age pigment” and is considered a hallmark of aging. This is not only because the amount of lipofuscin increases with age, showing an approximately linear dependence, but also, and more importantly, because the rate of lipofuscin accumulation correlates negatively with longevity [1, 12, 13, 16, 21].
Lipofuscin, or age pigment, represents an intra-lysosomal polymeric material that cannot be degraded by lysosomal hydrolases. Although its continuous accumulation over time in post-mitotic cells, such as neurons and cardiomyocytes, has been known for more than 100 years, it has recently been suggested that accumulated lipofuscin may be hazardous to cellular functions [1, 5, 24]. There are strong indications that progressive deposition of lipofuscin ultimately decreases cellular adaptability and promotes the development of age-related pathologies, including neuro-degenerative diseases, heart failure, and macular degeneration [5, 24]. T. Von Zglinicki et al. [27]. found that accelerated lipofuscin accumulation is sufficient to block cellular proliferation within a short period time and induce cell death. They concluded that accumulation of lipofuscin in post-mitotic cells is not just a harmless consequence of ageing, but rather one of the most important causes of senescence.
Some researchers believe that the accumulation of lipofuscin within post-mitotic cells occurs primarily because it is non-degradable and cannot be removed from the cells through exocytosis [19, 23].
However, previous studies have shown that lipofuscin might be released from tissues or cells. A study by E.F. El-Ghazzawi et al. [2] strongly suggested that nerve cells physiologically remove lipofuscin into the capillary endothelium. Upon treatment with meclofenoxate, there is a gradual decrease in the volume of the pigment in the myocardium. After a treatment period of 4–6 weeks, the pigment bodies were found to be lodged in the capillary endothelium and the lumen, which facilitates the removal of the pigment through the blood stream [15]. I. Joris et al. [7] observed the formation and outcome of lipofuscin in human coronary endothelium, and showed that the bulging cell processes containing lipofuscin probably eventually break off and are shed into the bloodstream. Similarly, it has also been proposed that neuronal lipofuscin was transported to the capillary wall and extruded into the lumen in the avian brain [18]. However, some researchers have questioned the studies showing the exclusion of lipofuscin from tissues [9].
Hence, it is still not conclusive whether the non-dividing cells in tissues and organs possess a mechanism for excluding lipofuscin. To ascertain whether the heart has a mechanism for eliminating lipofuscin from the myocardium, we carried out investigations using the mouse heart.
MATERIALS AND METHODS
Six 5-month-old Balb/c mice, equal males and females, weighing from 28.4 to 31.1 g (29.8 ± 0.9 g) were purchased and fed in SPF environment in Laboratory Animal Center of our institution. In order to meet the requirements of other studies on animal specimens, we selected animals to be taken under anesthesia. All surgery was performed under diethyl ether, and all efforts were made to minimize suffering. The hearts were removed. Small tissue blocks were obtained from the anterior wall of the left ventricle and were fixed with 1.5% glutaraldehyde. The fixed tissue blocks were further treated with 1% osmium tetroxide, dehydrated, and embedded in epoxy resin. The specimens were sliced using the Microm HM340E rotary ultramicrotome produced by Leica Microsystems Heidelberg GmbH in Germany, and the ultra-thin sections were placed on a copper screen and stained again using lead nitrate and uranyl acetate. Finally, specimens were observed with a Hitachi 7500 transmission electron microscope, and images were acquired using an AMT XR401 side insertion drawing equipment produced by Advanced Microscopy Techniques in USA.
RESULTS AND DISCUSSION
Myocardial Fibers (Cardiac Cells)
Microscopic observation of myocardial tissue revealed clearly visible lipofuscin deposits that were scattered around the myocardial fibers (cardiac cells) and myocardial interstitium. These lipid-like deposits were granular or agglomerated; widely varied in size and form; displayed high or medium electron density; uniform or uneven internal structure; or lamellar or lipid droplets; with or without membrane coating; or dispersed or aggregated into large clumps.
Lipofuscin found in the myocardial fibers was mainly distributed in the cytoplasm-rich regions at both ends of the nucleus and was interspersed between a large numbers of mitochondria. The distribution of lipofuscin granules was lower in the myofibrils that were far from the nucleus (Fig. S1). Lipofuscin granules could also be seen at the edges of myocardial fibers and below the sarcolemma (Figs. 8, S2, S9).
Compared with the lipofuscin granules located deep in the cardiomyocytes, the granules located around the cardiomyocytes were significantly smaller. The sarcolemma on the surface of cardiomyocytes was clearly visible, but often displayed unevenness. Bulging, rod-, sac-, or capsule-like protrusions of different sizes and lengths, were often observed, which contained the lipofuscin granules (Figs. 1–3, S3).
Cells in Myocardial Interstitium
In addition to being rich in capillaries, the interstitial space between myocardial fibers also had two types of cells, fibroblasts and macrophages, with fibroblasts being the predominant type.
Fibroblasts are slender spindle-shaped cells and their cell bodies extend along the longitudinal direction of the myocardial fibers with both their ends stretching far. The surface of fibroblast is smooth with no visible phagocytosis. Fibroblasts have a dense cytoplasmic structure and abundant organelles, which contain abundant rough endoplasmic reticulum, free ribosomes, and mitochondria (Figs. 4, S4–S6).
In addition, they also contain a large number of lipofuscin granules or clumps of varying sizes and shapes. The elongated cytoplasmic ends of the fibroblasts contain the lipofuscin granules or clumps, which can adhere to the capillaries and fall off. The structural density of the shed cytoplasm at the end of fibroblasts is higher, with higher electron density, and often has structural characteristics that are similar to lipofuscin (Figs. 5, S4–S6). The basement membrane outside the capillary vessel wall, which is in close contact with the cytoplasm of fibroblasts, often disappears, such that the shed cytoplasm can directly adhere to and fuse with the endothelial cells.
Macrophages are primarily oblong in shape and possess rough surface with several wrinkles or protrusions of different sizes, visibly exhibiting swallowing, phagocytosing and encapsulation of large granules. The internal structure of the cytoplasm is relatively loose and contains abundant vesicles, phagocytosed particles, and higher number of lipid droplet-like lipofuscin granules. These lipofuscin granules vary widely in size, internal structure, and electron density (Figs. 4, S6, S7).
Macrophages can either be closely attached to the capillaries through their cell body directly or through the cytoplasm that is elongated and shed. The density of the cytoplasmic fragments shed from the cytoplasmic end of the macrophages is relatively low, and the interior mainly consists of sparse fine particles, vesicles, and lipofuscin granules. The basement membrane outside the capillaries where the macrophages are in close contact with the capillary wall is incomplete or even absent (Figs. 3, 4, 6, 7). No macrophages were observed in and out of the capillaries or lymphatic vessels.
Matrix in Myocardial Interstitium
In the interstitial matrix of the myocardial space, a large number of non-cellular structured membrane-like structures can be seen, which can be of different sizes and electron density. They form loose, irregular sac-like structures with single or several layers, or dense myelin figures with multiple layers, creating complex structures that greatly vary in size, density, morphology and number of membrane layers (Figs. 2, 3, 5–8, S4). We termed these complex membrane-like structures as “membrane-like garbage.” These “membrane-like garbage” are widely and irregularly distributed in the matrix of the myocardial interstitium, either sparsely or densely.
In the interstitium, some free lipofuscin particles can also be seen that vary widely in size. Some are in the form of small granules, while others form large masses, which might be either coated or uncoated at the periphery (Fig. 8). Large clumps formed by the aggregation of several lipofuscin granules are sometimes seen (Fig. S8). Some lipofuscin granules have low density and a relatively loose structure. The shape is similar to the high-density “membrane-like garbage,” and there is no obvious morphological boundary as that seen in the “membrane garbage,” which is denser in structure (Figs. 2, 3, 5–8).
Capillaries in Myocardial Interstitium
There are many capillaries in the myocardial interstitium, which are continuous in nature. These capillaries can be roughly divided into two types: high density and low density endothelial cell types.
High-density endothelial cell-type capillary vessels have thick walls and high cytoplasmic density. Endothelial cells can form tight junctions. In addition to the scattered mitochondria inside the cytoplasm of the endothelial cells, they contain abundant pinocytotic vesicles and exocytosis vesicles. These vesicles are often highly dense, indicating that active transport occurs through their walls. High electron density granules and fine particles are found abundantly in the cytoplasm (Figs. 1, 3–7, 9, S2, S5).
The walls of low-density endothelial cell-type capillaries are thinner with relatively less dense cytoplasm. The number of vesicles is low, and few large vesicles and slender membrane tubules can also be seen. The cytoplasm contains many small particles with medium to high electron density, which can adhere to the membrane tube, with morphology similar to the rough endoplasmic reticulum (Figs. 8, 9, S9).
Morphologically, these two types of capillaries do not have clear boundaries, and the morphology of some vessels is somewhere in between. The endothelial cell membrane on the lumen side of most capillaries has small conical or tiny finger-like protrusions that are of different lengths and can be extruded into the lumen (Figs. 8, 9, S2, S5, S9). The cytoplasms of some endothelial cells are embedded with lipofuscin-like granules of different sizes and shapes (Figs. 3, 8, 9, S7, S9). Occasionally, these granules are embedded into the endothelial cells of the vessel walls from the exterior of the vessel without any basement membrane (Figs. 3, 6, and S9). It can also be seen that the lipofuscin granules in the myelin figure are extruded by the endothelial cells into the lumen from the walls of the vessels (Fig. 10).
“Membrane-like garbage” similar to that found in the myocardial stroma were seen within the lumen of some of the capillaries, which forms sac-like structures formed in the capillary cavity that is more loose and fragmented than the membrane-like garbage formed in the myocardial matrix. The amount of membrane-like garbage in the lumen varies between different blood vessels, and sometimes, there are very obvious differences between the two accompanying blood vessels (Figs. 1, 3–9, S2, S5, S9). In general, the lumens of the low-density endothelial-type capillaries contain significantly higher amount of membrane-like garbage than the high-density endothelial-type capillaries. This might be because the high-density endothelial-type capillaries are arterial-end capillaries, while low-density endothelial-type capillaries are venous-end capillaries. The blood flowing in the capillaries at the venous end collects more lipofuscin-like substances that are discharged from the capillary walls.
Capillary vessels are often surrounded by cell bodies or cytoplasmic fragments of different cell types, which can even be directly attached to the vessel wall. The areas where the extravessel cell body or cytoplasmic fragment is in contact with the capillary vessel wall, the basement membrane is often incomplete or even disappears, resulting in direct contact between the extravessel cytoplasm with the endothelial cells, which leads to blurring of the boundaries between them, and even merging. Extravessel cytoplasmic fragments often contain lipofuscin granules (Figs. 3, 4, 6, 7, S5, S9), or are in a highly dense formation (Figs. 1, 5, 9, S5, S9).
Pericytes were not observed around the capillaries. All the cytoplasmic fragments that are outside or surround the capillary walls, and even fuse with endothelial cells, are derived from the extended terminal cytoplasms of the macrophages and fibroblasts, or shed cytoplasmic debris.
Do the heart, brain, and retina have the ability to expel the accumulated lipofuscin? Is it possible to speed up the elimination of lipofuscin in these tissues with drugs such as centrophenoxine and meclofenoxate in order to slow down aging? These are some controversial questions [1, 2, 10, 14, 15, 22–24]. Therefore, this study investigates the elimination of lipofuscin from the heart to obtain potential evidence that lipofuscin is excreted by the tissues. These results might facilitate future research on related interventions.
Observation of myocardial cells revealed that these cells can eliminate lipofuscin. The mechanism of removal of the lipofuscin granules that are located below the sarcolemma might be via the formation of capsule-like protrusions on the sarcolemma and on the sarcoplasm near them, which extend into the interstitial space, detach from the myocardial cells and finally, enter the interstitial space. We did not observe exocytosis of large lipofuscin granules (approximately 1 µm diameter) in the myocardial fibers. This result may indicate that myocardial cells slowly and continuously excrete lipofuscin to the outside in a more subtle way.
Most of the lipofuscin particles entering the interstitium will soon disintegrate, de-aggregate, and diffuse, forming “membrane-like garbage” or mini soluble particles, which are dispersed in the interstitial matrix and diffuse around the blood vessels. These particles can enter the vascular wall of the endothelium through simple diffusion, pinocytosis of capillary endothelium, followed by further diffusion into the bloodstream; or be directly released into the bloodstream by exocytosis. Some mini lipofuscin particles can be adsorbed and fused with other membranous structures (lumen cell membrane, tubules, and vesicles) in the cytoplasm. The vesicles and tubules that fuse with lipofuscin will also merge into the surface membrane of endothelial cell lumen. It cannot be excluded that the mini soluble lipofuscin particles that have diffused into the endothelial cells re-aggregate in the endothelial cytoplasm to form larger lipofuscin granules, which are then “pushed” into the lumen by endothelial cells. This is similar to the phenomenon observed by I. Joris et al. in human coronary artery where it was seen that endothelial lipofuscin is excreted through enlarged cell processes [7]. A few of the smaller undisintegrated lipofuscin granules might be directly embedded into the capillary endothelium in the form of granules, and then enter the lumen in a “pushed” mode.
Lipofuscin masses in the macrophages might have arisen from three possible ways. First, it might be derived from phagocytosis of intact lipofuscin granules in the matrix. Second, it might be due to micro-engulfing of “membrane-like garbage” along with micro-phagocytosis of fine particles formed by de-aggregation of lipofuscin. These swallowed lipid molecules and phagocytosed particles then aggregate in the cell to form large lipofuscin granules or mass. Third, it might be due to phagocytosis and digestion of other cellular and tissue structural fragments in the cardiac interstitium. The lipofuscin formed through these three methods will eventually aggregate in the macrophages, forming huge lipofuscin masses.
How do macrophages containing large amounts of lipofuscin transfer lipofuscin away from the myocardial tissue? According to our observations and speculations, one of the most significant ways is to transport lipofuscin into the lumen of the blood vessel through fusion with capillary endothelial cells. Thus, the end of the elongated cytoplasm containing lipofuscin granules is close to the capillaries, and it eventually fuses with endothelial cells releasing the lipofuscin granules into the cytoplasm of endothelial cells. The lipofuscin granules entering the vessel wall are transported by the endothelial cells into the lumen in a “pushed” mode, thereby completing the process of transferring lipofuscin from the extravessel stroma into the lumen (Fig. 11).
The lipofuscin mass present in the fibroblasts might exist due to two reasons; one is due to the production of its own cell metabolism and the other is due to microphagocytosis, similar to the macrophages. Previous studies have shown that fibroblasts in the myocardial tissue possess a certain phagocytic function [3, 27]. However, in the present study, we did not observe engulfment of lipofuscin granules by the fibroblasts. Fibroblasts also seem to have the ability to excrete lipofuscin and similar to that seen in macrophages, it is excreted into blood vessels by fusion with capillary endothelial cells. Thus, the elongated cytoplasmic ends containing lipofuscin granules is close to the capillaries and fuses with endothelial cells, which releases the lipofuscin material into the cytoplasm of endothelial cells, and finally into their lumen in a “pushed” manner.
As the myocardial tissues we observed are located in the deeper regions of the heart wall, only capillaries that extend between the myocardial fibers, close to the myocardial fibers were visualized, along with a few connective tissues. Therefore, the pericytes or mast cells that were described by other researchers were not observed around the capillaries in our specimens [4].
Comparison of the amount of “membrane-like garbage” in different capillary lumens showed that myocardial tissues “dump” a large amount of “garbage” into the bloodstream during the blood flow, which is mainly derived from lipofuscin produced from myocardial cells, and this dumping is not slow. According to our observations, there are several modes of transport of lipofuscin in the myocardium through the capillary wall (Fig. 11). Although there are many modes of transfer, the in-wall and out-wall modes of these transfers are not a fixed combination, and there can be different combinations between different in-wall and out-wall modes. However, from the frequency shown by various transport modes, the cross-wall transport of lipofuscin in myocardial tissue may mainly rely on a small, fine, soluble, continuous transport mode, it is not a one-time, massive, or cell-carrying transfer. This small, fine, soluble, continuous transport pattern is slightly similar to the lipofuscin elimination phenomenon observed in the seminiferous tubules of animal testes [25, 26].
Many previous studies have described the presence of lymphatic vessels in the myocardium [20]. However, in the current study, lymphatic vessels with typical structural features were not observed. It is therefore uncertain whether a lipofuscin excretion pathway through the lymphatic vessels exists. This is completely different from the case where the lipofuscin discharged directly into the lymphatic ducts is observed in the testicular seminiferous tubules [25, 26].
Lipofuscin produced in tissues and organs may be carried away from tissues and organs by blood flow and enter the blood circulation system. S.V. Rizou et al. have demonstrated that lipofuscin can be isolated from blood plasma [17]. Our images show differences in the amount of “membrane-like garbages” or lipofuscin-like substances in some vessels and support the findings of S.V. Rizou et al.
In this study, we observed that some of the lipofuscin particles were transferred within the myocardial tissue; and across the capillary wall into the blood flow. However, there are still some unanswered questions, such as, is lipofuscin mainly transported in a soluble manner in the myocardium [6]? Is it possible to remove the lipofuscin present in the form of huge clumps? How is it cleared? What roles do fibroblasts play in the elimination of lipofuscin in the myocardium? Do the myocardial tissues from different parts of the mice heart treat lipofuscin in the same way? Further investigations are needed to answer these questions.
The authors would like to thanks professor Dr. Yuan Ding and professor Dr. Zhang Chang-Cheng for sharing the experimental materials. The authors would also like to thank professor Dr. Yang Jun and professor Dr. Yang Jian for their help in the use of the experimental platform.
Change history
22 December 2022
An Erratum to this paper has been published: https://doi.org/10.1134/S2079057022310010
REFERENCES
Brunk, U.T. and Terman, A., Lipofuscin: mechanisms of age-related accumulation and influence on cell function, Free Radic. Biol. Med., 2002, vol. 33, no. 5, рр. 611–619.
El-Ghazzawi, E.F. and Malaty, H.A., Electron microscopic observations on extraneuronal lipofuscin in the monkey brain, Cell Tissue Res., 1975, vol. 161, no. 4, рр. 555–565.
Elleder, M., Drahota, Z., Lisa, V., et al., Tissue culture loading test with storage granules from animal models of neuronal ceroid-lipofuscinosis (Batten disease): testing their lysosomal degradability by normal and Batten cells, Am. J. Med. Genet., 1995, vol. 57, no. 2, рр. 213–221.
Gersch, C., Dewald, O., Zoerlein, M., et al., Mast cells and macrophages in normal C57/BL/6 mice, Histochem. Cell Biol., 2002, vol. 118, no. 1, pp. 41–49.
Höhn, A. and Grune, T., Lipofuscin: formation, effects and role of macroautophagy, Redox. Biol., 2013, vol. 1, no. 1, рр. 140–144.
Jolly, R.D., Palmer, D.N., and Dalefield, R.R., The analytical approach to the nature of lipofuscin (age pigment), Arch. Gerontol. Geriatr., 2002, vol. 34, no. 3, рр. 205–217.
Joris, I., Billingham, M.E., Underwood, J.M., and Majno, G., Lipofuscin and lipid oxidation in human coronary endothelium, Cardiovasc. Pathol., 1998, vol. 7, no. 2, рр. 75–85.
Kakimoto, Y., Okada, C., Kawabe, N., et al., Myocardial lipofuscin accumulation in ageing and sudden cardiac death, Sci. Rep., 2019, vol. 9, no. 1, р. 3304.
Katz, M.L., Potential reversibility of lipofuscin accumulation, Arch. Gerontol. Geriatr., 2002, vol. 34, no. 3, рр. 311–317.
Katz, M.L., Rice, L.M., and Gao, C., Reversible accumulation of lipofuscin-like inclusions in the retinal pigment epithelium, Invest. Ophthalmol. Vis. Sci., 1999, vol. 40, no. 1, рр. 171–181.
Malkoff, D.B. and Strehler, B.L., The ultrastructure of isolated and in situ human cardiac age pigment, J. Cell Biol., 1963, vol. 16, no. 3, рр. 611–616.
Munnel, J.F. and Getty, R., Rate of accumulation of cardiac lipofuscin in the aging canine, J. Gerontol., 1968, vol. 23, no. 2, рр. 154–158.
Nakano, M. and Gotoh, S., Accumulation of cardiac lipofuscin depends on metabolic rate of mammals, J. Gerontol., 1992, vol. 47, no. 4, рр. В126–В129.
Nandy, K. and Bourne, G.H., Effect of centrophenoxine on the lipofuscin pigments in the neurones of senile Guinea-pigs, Nature, 1966, vol. 210, no. 5033, рр. 313–314.
Patro, N., Sharma, S.P., and Patro, L.K., Lipofuscin accumulation in ageing myocardium and its removal by meclophenoxate, Indian J. Med. Res., 1992, vol. 96, рр. 192–198.
Porta, E.A., Pigments in aging: an overview, Ann. N.Y. Acad. Sci., 2002, vol. 959, no. 1, рр. 57–65.
Rizou, S.V., Evangelou, K., Myrianthopoulos, V., et al., A novel quantitative method for the detection of lipofuscin, the main by-product of cellular senescence, in fluids, in Cellular Senescence: Methods and Protocols, Demaria, M., Ed., New York, N.Y.: Springer New York, 2019, vol. 1896, pp. 119–138.
Singh, R. and Mukherjee, B., Some observations of the lipofuscin of the avian brain with a review of some rarely considered finding concerning the metabolic and physiologic significance of the neuronal lipofuscin, Acta. Anat., 1972, vol. 83, no. 1, рр. 302–320.
Sitte, N., Huber, M., Grune, T., et al., Proteasome inhibition by lipofuscin/ceroid during postmitotic aging of fibroblasts, FASEB J., 2000, vol. 14, no. 11, рр. 1490–1498.
Sommer, J.R. and Jennings, R.B., Ultrastructure of cardiac muscle, in The Heart and Cardiovascular System, Fozzard, H.A., Haber, E., Jennings, R.B., et al., Eds., New York: Reven Press, 1991, vol. I. 2nd ed., pp. 3–50.
Strehler, B.L., Mark, D.D., Mildvan, A.S., and Gee, M.V., Rate of magnitude of age pigment accumulation in the human myocardium, J. Gerontol., 1959, vol. 14, pp. 430–439.
Terman, A. and Brunk, U.T., Ceroid/lipofuscin formation in cultured human fibroblasts: the role of oxidative stress and lysosomal proteolysis, Mech. Ageing Dev., 1998a, vol. 104, no. 3, pp. 277–291.
Terman, A. and Brunk, U.T., On the degradability and exocytosis of ceroid/lipofuscin in cultured rat cardiac myocytes, Mech. Ageing Dev., 1998b, vol. 100, no. 100, pp. 145–156.
Terman, A. and Brunk, U.T., Lipofuscin, Int. J. Biochem. Cell Biol., 2004, vol. 36, no. 8, pp. 1400–1404.
Xiao, C.Y., Wang, Y.Q., Li, J.H., and Tang, G.C., Formation and outcome of residual bodies in seminiferous tubules of the mouse testis, Acta. Med. Univ. Sci. Technol. Huazhong, 2016, vol. 45, no. 5, pp. 529–534.
Xiao, C.Y., Wang, Y.Q., Li, J.H., et al., Transformation, migration and outcome of residual bodies in the seminiferous tubules of the rat testis, Andrologia, 2017, vol. 49, no. 10, pp. e12786–e12795.
Von Zglinicki, T., Nilsson, E., Docke, W.D., and Brunk, U.T., Lipofuscin accumulation and ageing of fibroblasts, Gerontology, 1995, vol. 41, suppl. 2, pp. 95–108.
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Wang, L., Xiao, CY., Li, JH. et al. Transport and Possible Outcome of Lipofuscin in Mouse Myocardium. Adv Gerontol 12, 247–263 (2022). https://doi.org/10.1134/S207905702203016X
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DOI: https://doi.org/10.1134/S207905702203016X